Substituted pyrazino[2,3-b]pyrazines as mTOR kinase inhibitors

ABSTRACT

Provided herein are Heteroaryl Compounds having the following structure: 
     
       
         
         
             
             
         
       
         
         
           
             wherein R 1 -R 4  are as defined herein, compositions comprising an effective amount of a Heteroaryl Compound and methods for treating or preventing cancer, inflammatory conditions, immunological conditions, neurodegenerative diseases, diabetes, obesity, neurological disorders, age-related diseases, or cardiovascular conditions, comprising administering an effective amount of a Heteroaryl Compound to a patient in need thereof. 
           
         
       
    
     Furthermore, provided are methods of preparing a compound of formula (III), 
     
       
         
         
             
             
         
       
     
     Furthermore, provided are methods of preparing a compound of formula (VI),

1. CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.13/295,513, filed Nov. 14, 2011, currently allowed, which is acontinuation of U.S. application Ser. No. 12/605,791, filed Oct. 26,2009, now U.S. Pat. No. 8,110,578, issued Feb. 7, 2012, which claims thebenefit of U.S. Provisional Application No. 61/108,627, filed Oct. 27,2008, the entire contents of each of which are incorporated herein byreference.

2. BACKGROUND

Provided herein are certain heteroaryl compounds, compositionscomprising an effective amount of one or more such compounds and methodsfor treating or preventing cancer, inflammatory conditions,immunological conditions, metabolic conditions and conditions treatableor preventable by inhibition of a kinase pathway, comprisingadministering an effective amount of a heteroaryl compound to a patientin need thereof.

The connection between abnormal protein phosphorylation and the cause orconsequence of diseases has been known for over 20 years. Accordingly,protein kinases have become a very important group of drug targets. SeeCohen, Nature, 1:309-315 (2002). Various protein kinase inhibitors havebeen used clinically in the treatment of a wide variety of diseases,such as cancer and chronic inflammatory diseases, including diabetes andstroke. See Cohen, Eur. J. Biochem., 268:5001-5010 (2001).

The protein kinases are a large and diverse family of enzymes thatcatalyze protein phosphorylation and play a critical role in cellularsignaling. Protein kinases may exert positive or negative regulatoryeffects, depending upon their target protein. Protein kinases areinvolved in specific signaling pathways which regulate cell functionssuch as, but not limited to, metabolism, cell cycle progression, celladhesion, vascular function, apoptosis, and angiogenesis. Malfunctionsof cellular signaling have been associated with many diseases, the mostcharacterized of which include cancer and diabetes. The regulation ofsignal transduction by cytokines and the association of signal moleculeswith protooncogenes and tumor suppressor genes have been welldocumented. Similarly, the connection between diabetes and relatedconditions, and deregulated levels of protein kinases, has beendemonstrated. See e.g., Sridhar et al. Pharmaceutical Research,17(11):1345-1353 (2000). Viral infections and the conditions relatedthereto have also been associated with the regulation of proteinkinases. Park et al. Cell 101 (7): 777-787 (2000).

Protein kinases can be divided into broad groups based upon the identityof the amino acid(s) that they target (serine/threonine, tyrosine,lysine, and histidine). For example, tyrosine kinases include receptortyrosine kinases (RTKs), such as growth factors and non-receptortyrosine kinases, such as the src kinase family. There are alsodual-specific protein kinases that target both tyrosine andserine/threonine, such as cyclin dependent kinases (CDKs) andmitogen-activated protein kinases (MAPKs).

Because protein kinases regulate nearly every cellular process,including metabolism, cell proliferation, cell differentiation, and cellsurvival, they are attractive targets for therapeutic intervention forvarious disease states. For example, cell-cycle control andangiogenesis, in which protein kinases play a pivotal role are cellularprocesses associated with numerous disease conditions such as but notlimited to cancer, inflammatory diseases, abnormal angiogenesis anddiseases related thereto, atherosclerosis, macular degeneration,diabetes, obesity, and pain.

Protein kinases have become attractive targets for the treatment ofcancers. Fabbro et al., Pharmacology & Therapeutics 93:79-98 (2002). Ithas been proposed that the involvement of protein kinases in thedevelopment of human malignancies may occur by: (1) genomicrearrangements (e.g., BCR-ABL in chronic myelogenous leukemia), (2)mutations leading to constitutively active kinase activity, such asacute myelogenous leukemia and gastrointestinal tumors, (3) deregulationof kinase activity by activation of oncogenes or loss of tumorsuppressor functions, such as in cancers with oncogenic RAS, (4)deregulation of kinase activity by over-expression, as in the case ofEGFR and (5) ectopic expression of growth factors that can contribute tothe development and maintenance of the neoplastic phenotype. Fabbro etal., Pharmacology & Therapeutics 93:79-98 (2002).

The elucidation of the intricacy of protein kinase pathways and thecomplexity of the relationship and interaction among and between thevarious protein kinases and kinase pathways highlights the importance ofdeveloping pharmaceutical agents capable of acting as protein kinasemodulators, regulators or inhibitors that have beneficial activity onmultiple kinases or multiple kinase pathways. Accordingly, there remainsa need for new kinase modulators.

The protein named mTOR (mammalian target of rapamycin), which is alsocalled FRAP, RAFTI or RAPT1), is a 2549-amino acid Ser/Thr proteinkinase, that has been shown to be one of the most critical proteins inthe mTOR/PI3K/Akt pathway that regulates cell growth and proliferation.Georgakis and Younes Expert Rev. Anticancer Ther. 6(1):131-140 (2006).mTOR exists within two complexes, mTORC1 and mTORC2. mTORC1 is sensitiveto rapamycin analogs (such as temsirolimus or everolimus) and mTORC2 islargely rapamycin-insensitive. Several mTOR inhibitors have been or arebeing evaluated in clinical trials for the treatment of cancer.Temsirolimus was approved for use in renal cell carcinoma in 2007 andeverolimus was approved in 2009 for renal cell carcinoma patients thathave progressed on vascular endothelial growth factor receptorinhibitors. In addition, sirolimus was approved in 1999 for theprophylaxis of renal transplant rejection. The interesting but limitedclinical success of these mTORC1 compounds demonstrates the usefulnessof mTOR inhibitors in the treatment of cancer and transplant rejection,and the increased potential for compounds with both mTORC1 and mTORC2inhibitory activity.

Citation or identification of any reference in Section 2 of thisapplication is not to be construed as an admission that the reference isprior art to the present application.

3. SUMMARY

Provided herein are compounds having the following formula (I):

and pharmaceutically acceptable salts, clathrates, solvates, tautomers,stereoisomers and prodrugs thereof, wherein R¹-R⁴ are as defined herein.

Further provided herein are compounds having the following formula (II):

and pharmaceutically acceptable salts, clathrates, solvates, tautomers,stereoisomers and prodrugs thereof, wherein R¹, R² and R³ are as definedherein.

Compounds of formula (I) and (II), or pharmaceutically acceptable salts,clathrates, solvates, hydrates, stereoisomers, tautomers, or prodrugsthereof (each being referred to herein as “Heteroaryl Compounds”), areuseful for treating or preventing cancer, inflammatory conditions,immunological conditions, neurodegenerative diseases, diabetes, obesity,neurological disorders, age-related diseases, and cardiovascularconditions, and conditions treatable or preventable by inhibition of akinase pathway. In one embodiment, the kinase pathway is themTOR/PI3K/Akt pathway. In another embodiment, the kinase pathway is thePI3Kα, PI3Kβ, PI3Kδ, KDR, GSK3α, GSK3β, ATM, ATX, ATR, cFMS, and/orDNA-PK pathway.

Further provided herein are compositions comprising an effective amountof a Heteroaryl Compound and compositions comprising an effective amountof a Heteroaryl Compound and a pharmaceutically acceptable carrier orvehicle. The compositions are useful for treating or preventing cancer,inflammatory conditions, immunological conditions, neurodegenerativediseases, diabetes, obesity, neurological disorders, age-relateddiseases, or cardiovascular conditions and conditions treatable orpreventable by inhibition of a kinase pathway, in one embodiment, themTOR/PI3K/Akt pathway.

Further provided herein are methods for treating or preventing cancer,inflammatory conditions, immunological conditions, neurodegenerativediseases, diabetes, obesity, neurological disorders, age-relateddiseases, or cardiovascular conditions and conditions treatable orpreventable by inhibition of a kinase pathway, in one embodiment, themTOR/PI3K/Akt pathway, comprising administering an effective amount of aHeteroaryl Compound to a patient in need of the treating or preventing.

Also provided herein are methods for inhibiting a kinase in a cellexpressing said kinase, comprising contacting the cell with an effectiveamount of a Heteroaryl Compound as described herein. In one embodimentthe kinase is mTOR, DNA-PK, or PI3K or a combination thereof.

The present embodiments can be understood more fully by reference to thedetailed description and examples, which are intended to exemplifynon-limiting embodiments.

4. DETAILED DESCRIPTION 4.1 Definitions

An “alkyl” group is a saturated, partially saturated, or unsaturatedstraight chain or branched non-cyclic hydrocarbon having from 1 to 10carbon atoms, typically from 1 to 8 carbons or, in some embodiments,from 1 to 6, 1 to 4, or 2 to 6 or carbon atoms. Representative alkylgroups include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl and-n-hexyl; while saturated branched alkyls include -isopropyl,-sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl and the like. Examplesof unsaturared alkyl groups include, but are not limited to, vinyl,allyl, —CH═CH(CH₃), —CH═C(CH₃)₂, —C(CH₃)═CH₂, —C(CH₃)═CH(CH₃),—C(CH₂CH₃)═CH₂, —C≡CH, —C≡C(CH₃), —C≡C(CH₂CH₃), —CH₂C≡CH, —CH₂C≡C(CH₃)and —CH₂C≡C(CH₇CH₃), among others. An alkyl group can be substituted orunsubstituted.

A “cycloalkyl” group is a saturated, partially saturated, or unsaturatedcyclic alkyl group of from 3 to 10 carbon atoms having a single cyclicring or multiple condensed or bridged rings which can be optionallysubstituted with from 1 to 3 alkyl groups. In some embodiments, thecycloalkyl group has 3 to 8 ring members, whereas in other embodimentsthe number of ring carbon atoms ranges from 3 to 5, 3 to 6, or 3 to 7.Such cycloalkyl groups include, by way of example, single ringstructures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl,2-methylcyclooctyl, and the like, or multiple or bridged ring structuressuch as adamantyl and the like. Examples of unsaturared cycloalkylgroups include cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl,pentadienyl, hexadienyl, among others. A cycloalkyl group can besubstituted or unsubstituted. Such substituted cycloalkyl groupsinclude, by way of example, cyclohexanone and the like.

An “aryl” group is an aromatic carbocyclic group of from 6 to 14 carbonatoms having a single ring (e.g., phenyl) or multiple condensed rings(e.g., naphthyl or anthryl). In some embodiments, aryl groups contain6-14 carbons, and in others from 6 to 12 or even 6 to 10 carbon atoms inthe ring portions of the groups. Particular aryls include phenyl,biphenyl, naphthyl and the like. An aryl group can be substituted orunsubstituted. The phrase “aryl groups” also includes groups containingfused rings, such as fused aromatic-aliphatic ring systems (e.g.,indanyl, tetrahydronaphthyl, and the like).

A “heteroaryl” group is an aryl ring system having one to fourheteroatoms as ring atoms in a heteroaromatic ring system, wherein theremainder of the atoms are carbon atoms. In some embodiments, heteroarylgroups contain 5 to 6 ring atoms, and in others from 6 to 9 or even 6 to10 atoms in the ring portions of the groups. Suitable heteroatomsinclude oxygen, sulfur and nitrogen. In certain embodiments, theheteroaryl ring system is monocyclic or bicyclic. Non-limiting examplesinclude but are not limited to, groups such as pyrrolyl, pyrazolyl,imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl,pyrolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl,benzothiophenyl, furanyl, benzofuranyl (for example,isobenzofuran-1,3-diimine), indolyl, azaindolyl (for example,pyrrolopyridyl or 1H-pyrrolo[2,3-b]pyridyl), indazolyl, benzimidazolyl(for example, 1H-benzo[d]imidazolyl), imidazopyridyl (for example,azabenzimidazolyl, 3H-imidazo[4,5-b]pyridyl or1H-imidazo[4,5-b]pyridyl), pyrazolopyridyl, triazolopyridyl,benzotriazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl,isoxazolopyridyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl,guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl,and quinazolinyl groups.

A “heterocyclyl” is an aromatic (also referred to as heteroaryl) ornon-aromatic cycloalkyl in which one to four of the ring carbon atomsare independently replaced with a heteroatom from the group consistingof O, S and N. In some embodiments, heterocyclyl groups include 3 to 10ring members, whereas other such groups have 3 to 5, 3 to 6, or 3 to 8ring members. Heterocyclyls can also be bonded to other groups at anyring atom (i.e., at any carbon atom or heteroatom of the heterocyclicring). A heterocycloalkyl group can be substituted or unsubstituted.Heterocyclyl groups encompass unsaturated, partially saturated andsaturated ring systems, such as, for example, imidazolyl, imidazolinyland imidazolidinyl groups. The phrase heterocyclyl includes fused ringspecies, including those comprising fused aromatic and non-aromaticgroups, such as, for example, benzotriazolyl,2,3-dihydrobenzo[1,4]dioxinyl, and benzo[1,3]dioxolyl. The phrase alsoincludes bridged polycyclic ring systems containing a heteroatom suchas, but not limited to, quinuclidyl. Representative examples of aheterocyclyl group include, but are not limited to, aziridinyl,azetidinyl, pyrrolidyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl,tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl,pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl,triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiazolinyl,isothiazolyl, thiadiazolyl, oxadiazolyl, piperidyl, piperazinyl,morpholinyl, thiomorpholinyl, tetrahydropyranyl (for example,tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathiane, dioxyl,dithianyl, pyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl,triazinyl, dihydropyridyl, dihydrodithiinyl, dihydrodithionyl,homopiperazinyl, quinuclidyl, indolyl, indolinyl, isoindolyl, azaindolyl(pyrrolopyridyl), indazolyl, indolizinyl, benzotriazolyl,benzimidazolyl, benzofuranyl, benzothiophenyl, benzthiazolyl,benzoxadiazolyl, benzoxazinyl, benzodithiinyl, benzoxathiinyl,benzothiazinyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl,benzo[1,3]dioxolyl, pyrazolopyridyl, imidazopyridyl (azabenzimidazolyl;for example, 1H-imidazo[4,5-b]pyridyl, or1H-imidazo[4,5-b]pyridin-2(3H)-onyl), triazolopyridyl, isoxazolopyridyl,purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl,quinolizinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl,naphthyridinyl, pteridinyl, thianaphthalenyl, dihydrobenzothiazinyl,dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxinyl,tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl,tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl,tetrahydropyrazolopyridyl, tetrahydroimidazopyridyl,tetrahydrotriazolopyridyl, and tetrahydroquinolinyl groups.Representative substituted heterocyclyl groups may be mono-substitutedor substituted more than once, such as, but not limited to, pyridyl ormorpholinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, ordisubstituted with various substituents such as those listed below.

An “cycloalkylalkyl” group is a radical of the formula:-alkyl-cycloalkyl, wherein alkyl and cycloalkyl are defined above.Substituted cycloalkylalkyl groups may be substituted at the alkyl, thecycloalkyl, or both the alkyl and the cycloalkyl portions of the group.Representative cycloalkylalkyl groups include but are not limited tocyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl,and cyclohexylpropyl. Representative substituted cycloalkylalkyl groupsmay be mono-substituted or substituted more than once

An “aralkyl” group is a radical of the formula: -alkyl-aryl, whereinalkyl and aryl are defined above. Substituted aralkyl groups may besubstituted at the alkyl, the aryl, or both the alkyl and the arylportions of the group. Representative aralkyl groups include but are notlimited to benzyl and phenethyl groups and fused (cycloalkylaryl)alkylgroups such as 4-ethyl-indanyl.

An “heterocyclylalkyl” group is a radical of the formula:-alkyl-heterocyclyl, wherein alkyl and heterocyclyl are defined above.Substituted heterocyclylalkyl groups may be substituted at the alkyl,the heterocyclyl, or both the alkyl and the heterocyclyl portions of thegroup. Representative heterocylylalkyl groups include but are notlimited to 4-ethyl-morpholinyl, 4-propylmorpholinyl, furan-2-yl methyl,furan-3-yl methyl, pyrdine-3-yl methyl,(tetrahydro-2H-pyran-4-yl)methyl, (tetrahydro-2H-pyran-4-yl)ethyl,tetrahydrofuran-2-yl methyl, tetrahydrofuran-2-yl ethyl, and indol-2-ylpropyl.

A “halogen” is fluorine, chlorine, bromine or iodine.

A “hydroxyalkyl” group is an alkyl group as described above substitutedwith one or more hydroxy groups.

An “alkoxy” group is —O-(alkyl), wherein alkyl is defined above.

An “alkoxyalkyl” group is -(alkyl)-O-(alkyl), wherein alkyl is definedabove.

An “amino” group is a radical of the formula: —NH₂.

An “alkylamino” group is a radical of the formula: —NH-alkyl or—N(alkyl)₂, wherein each alkyl is independently as defined above.

A “carboxy” group is a radical of the formula: —C(O)OH.

An “aminocarbonyl” group is a radical of the formula: —C(O)N(R^(#))₂,—C(O)NH(R^(#)) or —C(O)NH₂, wherein each R^(#) is independently asubstituted or unsubstituted alkyl, cycloalkyl, aryl, aralkyl,heterocyclyl or heterocyclyl group as defined herein.

An “acylamino” group is a radical of the formula: —NHC(O)(R^(#)) or—N(alkyl)C(O)(R^(#)), wherein each alkyl and R^(#) are independently asdefined above.

An “alkylsulfonylamino” group is a radical of the formula: —NHSO₂(R^(#))or —N(alkyl)SO₂(R^(#)), wherein each alkyl and R^(#) are defined above.

A “urea” group is a radical of the formula: —N(alkyl)C(O)N(R^(#))₂,—N(alkyl)C(O)NH(R^(#)), —N(alkyl)C(O)NH₂, —NHC(O)N(R^(#))₂,—NHC(O)NH(R^(#)), or —NH(CO)NHR^(#), wherein each alkyl and R^(#) areindependently as defined above.

In one embodiment, when the groups described herein are said to be“substituted,” they may be substituted with any appropriate substituentor substituents. Illustrative examples of substituents are those foundin the exemplary compounds and embodiments disclosed herein, as well ashalogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxyl; alkoxy;alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether;imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino;phosphonato; phosphine; thiocarbonyl; sulfonyl; sulfone; sulfonamide;ketone; aldehyde; ester; urea; urethane; oxime; hydroxylamine;alkoxyamine; aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone;azide; isocyanate; isothiocyanate; cyanate; thiocyanate; oxygen (═O);B(OH)₂, O(alkyl)aminocarbonyl; cycloalkyl, which may be monocyclic orfused or non-fused polycyclic (e.g., cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl), or a heterocyclyl, which may be monocyclicor fused or non-fused polycyclic (e.g., pyrrolidyl, piperidyl,piperazinyl, morpholinyl, or thiazinyl); monocyclic or fused ornon-fused polycyclic aryl or heteroaryl (e.g., phenyl, naphthyl,pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl,isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridinyl,quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl,pyrimidinyl, benzimidazolyl, benzothiophenyl, or benzofuranyl)aryloxy;aralkyloxy; heterocyclyloxy; and heterocyclyl alkoxy.

As used herein, the term “pharmaceutically acceptable salt(s)” refers toa salt prepared from a pharmaceutically acceptable non-toxic acid orbase including an inorganic acid and base and an organic acid and base.Suitable pharmaceutically acceptable base addition salts of theHeteroaryl Compounds include, but are not limited to metallic salts madefrom aluminum, calcium, lithium, magnesium, potassium, sodium and zincor organic salts made from lysine, N,N′-dibenzylethylenediamine,chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine(N-methylglucamine) and procaine. Suitable non-toxic acids include, butare not limited to, inorganic and organic acids such as acetic, alginic,anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethenesulfonic, formic, fumaric, furoic, galacturonic, gluconic,glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic,lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic,pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic,succinic, sulfanilic, sulfuric, tartaric acid, and p-toluenesulfonicacid. Specific non-toxic acids include hydrochloric, hydrobromic,phosphoric, sulfuric, and methanesulfonic acids. Examples of specificsalts thus include hydrochloride and mesylate salts. Others arewell-known in the art, see for example, Remington's PharmaceuticalSciences, 18^(th) eds., Mack Publishing, Easton Pa. (1990) or Remington:The Science and Practice of Pharmacy, 19^(th) eds., Mack Publishing,Easton Pa. (1995).

As used herein and unless otherwise indicated, the term “clathrate”means a Heteroaryl Compound, or a salt thereof, in the form of a crystallattice that contains spaces (e.g., channels) that have a guest molecule(e.g., a solvent or water) trapped within or a crystal lattice wherein aHeteroaryl Compound is a guest molecule.

As used herein and unless otherwise indicated, the term “solvate” meansa Heteroaryl Compound, or a salt thereof, that further includes astoichiometric or non-stoichiometric amount of a solvent bound bynon-covalent intermolecular forces. In one embodiment, the solvate is ahydrate.

As used herein and unless otherwise indicated, the term “hydrate” meansa Heteroaryl Compound, or a salt thereof, that further includes astoichiometric or non-stoichiometric amount of water bound bynon-covalent intermolecular forces.

As used herein and unless otherwise indicated, the term “prodrug” meansa Heteroaryl Compound derivative that can hydrolyze, oxidize, orotherwise react under biological conditions (in vitro or in vivo) toprovide an active compound, particularly a Heteroaryl Compound. Examplesof prodrugs include, but are not limited to, derivatives and metabolitesof a Heteroaryl Compound that include biohydrolyzable moieties such asbiohydrolyzable amides, biohydrolyzable esters, biohydrolyzablecarbamates, biohydrolyzable carbonates, biohydrolyzable ureides, andbiohydrolyzable phosphate analogues. In certain embodiments, prodrugs ofcompounds with carboxyl functional groups are the lower alkyl esters ofthe carboxylic acid. The carboxylate esters are conveniently formed byesterifying any of the carboxylic acid moieties present on the molecule.Prodrugs can typically be prepared using well-known methods, such asthose described by Burger's Medicinal Chemistry and Drug Discovery6^(th) ed. (Donald J. Abraham ed., 2001, Wiley) and Design andApplication of Prodrugs (H. Bundgaard ed., 1985, Harwood AcademicPublishers Gmfh).

As used herein and unless otherwise indicated, the term “stereoisomer”or “stereomerically pure” means one stereoisomer of a HeteroarylCompound that is substantially free of other stereoisomers of thatcompound. For example, a stereomerically pure compound having one chiralcenter will be substantially free of the opposite enantiomer of thecompound. A stereomerically pure compound having two chiral centers willbe substantially free of other diastereomers of the compound. A typicalstereomerically pure compound comprises greater than about 80% by weightof one stereoisomer of the compound and less than about 20% by weight ofother stereoisomers of the compound, greater than about 90% by weight ofone stereoisomer of the compound and less than about 10% by weight ofthe other stereoisomers of the compound, greater than about 95% byweight of one stereoisomer of the compound and less than about 5% byweight of the other stereoisomers of the compound, or greater than about97% by weight of one stereoisomer of the compound and less than about 3%by weight of the other stereoisomers of the compound. The HeteroarylCompounds can have chiral centers and can occur as racemates, individualenantiomers or diastereomers, and mixtures thereof. All such isomericforms are included within the embodiments disclosed herein, includingmixtures thereof. The use of stereomerically pure forms of suchHeteroaryl Compounds, as well as the use of mixtures of those forms areencompassed by the embodiments disclosed herein. For example, mixturescomprising equal or unequal amounts of the enantiomers of a particularHeteroaryl Compound may be used in methods and compositions disclosedherein. These isomers may be asymmetrically synthesized or resolvedusing standard techniques such as chiral columns or chiral resolvingagents. See, e.g., Jacques, J., et al., Enantiomers, Racemates andResolutions (Wiley-Interscience, New York, 1981); Wilen, S. H., et al.,Tetrahedron 33:2725 (1977); Eliel, E. L., Stereochemistry of CarbonCompounds (McGraw-Hill, NY, 1962); and Wilen, S. H., Tables of ResolvingAgents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of NotreDame Press, Notre Dame, Ind., 1972).

It should also be noted the Heteroaryl Compounds can include E and Zisomers, or a mixture thereof, and cis and trans isomers or a mixturethereof. In certain embodiments, the Heteroaryl Compounds are isolatedas either the cis or trans isomer. In other embodiments, the HeteroarylCompounds are a mixture of the cis and trans isomers.

“Tautomers” refers to isomeric forms of a compound that are inequilibrium with each other. The concentrations of the isomeric formswill depend on the environment the compound is found in and may bedifferent depending upon, for example, whether the compound is a solidor is in an organic or aqueous solution. For example, in aqueoussolution, pyrazoles may exhibit the following isomeric forms, which arereferred to as tautomers of each other:

As readily understood by one skilled in the art, a wide variety offunctional groups and other structures may exhibit tautomerism and alltautomers of compounds of formula (I) and formula (II) are within thescope of the present invention.

It should also be noted the Heteroaryl Compounds can contain unnaturalproportions of atomic isotopes at one or more of the atoms. For example,the compounds may be radiolabeled with radioactive isotopes, such as forexample tritium (³H), iodine-125 (¹²⁵I), sulfur-35 (³⁵S), or carbon-14(¹⁴C), or may be isotopically enriched, such as with deuterium (²H),carbon-13 (¹³C), or nitrogen-15 (¹⁵N). As used herein, an “isotopologue”is an isotopically enriched compound. The term “isotopically enriched”refers to an atom having an isotopic composition other than the naturalisotopic composition of that atom. “Isotopically enriched” may alsorefer to a compound containing at least one atom having an isotopiccomposition other than the natural isotopic composition of that atom.The term “isotopic composition” refers to the amount of each isotopepresent for a given atom. Radiolabeled and isotopically enrichedcompounds are useful as therapeutic agents, e.g., cancer andinflammation therapeutic agents, research reagents, e.g., binding assayreagents, and diagnostic agents, e.g., in vivo imaging agents. Allisotopic variations of the Heteroaryl Compounds as described herein,whether radioactive or not, are intended to be encompassed within thescope of the embodiments provided herein. In some embodiments, there areprovided isotopologues of the Heteroaryl Compounds, for example, theisotopologues are deuterium, carbon-13, or nitrogen-15 enrichedHeteroaryl Compounds.

“Treating” as used herein, means an alleviation, in whole or in part, ofsymptoms associated with a disorder or disease, or slowing, or haltingof further progression or worsening of those symptoms, or prevention orprophylaxis of the disease or disorder in a patient at risk fordeveloping the disease or disorder.

The term “effective amount” in connection with an Heteroaryl Compoundmeans an amount capable of alleviating, in whole or in part, symptomsassociated with a disorder or disease, or slowing or halting furtherprogression or worsening of those symptoms, or preventing or providingprophylaxis for the disease or disorder in a subject at risk fordeveloping the disease or disorder as disclosed herein, such as cancer,inflammatory conditions, immunological conditions, neurodegenerativediseases, diabetes, obesity, neurological disorders, age-relateddiseases, or cardiovascular conditions, and conditions treatable orpreventable by inhibition of a kinase pathway, for example, themTOR/PI3K/Akt pathway. In one embodiment an effective amount of aHeteroaryl Compound is an amount that inhibits a kinase in a cell, suchas, for example, in vitro or in vivo. In one embodiment the kinase ismTOR, DNA-PK, PI3K or a combination thereof. In some embodiments, theeffective amount of the Heteroaryl Compound inhibits the kinase in acell by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 99%, compared tothe activity of the kinase in an untreated cell. The effective amount ofthe Heteroaryl Compound, for example in a pharmaceutical composition,may be at a level that will exercise the desired effect; for example,about 0.005 mg/kg of a subject's body weight to about 100 mg/kg of apatient's body weight in unit dosage for both oral and parenteraladministration. As will be apparent to those skilled in the art, it isto be expected that the effective amount of an Heteroaryl Compounddisclosed herein may vary depending on the indication being treated,e.g., the effective amount of an Heteroaryl Compound would likely bedifferent for treating patients suffering from, or at risk for,inflammatory conditions relative to the effective amount of the Compoundfor treating patients suffering from, or at risk of, a differentdisorder, e.g., cancer or a metabolic disorder.

The term “patient” includes an animal, including, but not limited to, ananimal such as a cow, monkey, horse, sheep, pig, chicken, turkey, quail,cat, dog, mouse, rat, rabbit or guinea pig, in one embodiment a mammal,in another embodiment a human.

The term “cancer” refers to any of various malignant neoplasmscharacterized by the proliferation of cells that can invade surroundingtissue and metastasize to new body sites. Both benign and malignanttumors are classified according to the type of tissue in which they arefound. For example, fibromas are neoplasms of fibrous connective tissue,and melanomas are abnormal growths of pigment (melanin) cells. Malignanttumors originating from epithelial tissue, e.g., in skin, bronchi, andstomach, are termed carcinomas. Malignancies of epithelial glandulartissue such as are found in the breast, prostate, and colon, are knownas adenocarcinomas. Malignant growths of connective tissue, e.g.,muscle, cartilage, lymph tissue, and bone, are called sarcomas.Lymphomas and leukemias are malignancies arising among white bloodcells. Through the process of metastasis, tumor cell migration to otherareas of the body establishes neoplasms in areas away from the site ofinitial appearance. Bone tissues are one of the most favored sites ofmetastases of malignant tumors, occurring in about 30% of all cancercases. Among malignant tumors, cancers of the lung, breast, prostate orthe like are particularly known to be likely to metastasize to bone.

In the context of neoplasm, cancer, tumor growth or tumor cell growth,inhibition may be assessed by delayed appearance of primary or secondarytumors, slowed development of primary or secondary tumors, decreasedoccurrence of primary or secondary tumors, slowed or decreased severityof secondary effects of disease, arrested tumor growth and regression oftumors, among others. In the extreme, complete inhibition, is referredto herein as prevention or chemoprevention. In this context, the term“prevention” includes either preventing the onset of clinically evidentneoplasia altogether or preventing the onset of a preclinically evidentstage of neoplasia in individuals at risk. Also intended to beencompassed by this definition is the prevention of transformation intomalignant cells or to arrest or reverse the progression of premalignantcells to malignant cells. This includes prophylactic treatment of thoseat risk of developing the neoplasia.

4.2 Heteroaryl Compounds

Provided herein are compounds having the following formula (I):

and pharmaceutically acceptable salts, clathrates, solvates,stereoisomers, tautomers, and prodrugs thereof, wherein:

R¹ is substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted aryl, substituted or unsubstituted cycloalkyl, substitutedor unsubstituted heterocyclyl, or substituted or unsubstitutedheterocyclylalkyl;

R² is H, substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted heterocyclylalkyl, substituted orunsubstituted aralkyl, or substituted or unsubstituted cycloalkylalkyl;

R³ and R⁴ are each independently H, substituted or unsubstituted C₁₋₈alkyl, substituted or unsubstituted aryl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted heterocyclylalkyl, substituted or unsubstituted aralkyl,substituted or unsubstituted cycloalkylalkyl, or R³ and R⁴, togetherwith the atoms to which they are attached, form a substituted orunsubstituted cycloalkyl or substituted or unsubstituted heterocyclyl;

or R² and one of R³ and R⁴, together with the atoms to which they areattached, form a substituted or unsubstituted heterocyclyl;

provided the compound is not the compounds depicted below, namely:

6-(4-hydroxyphenyl)-4-(3-methoxybenzyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

6-(4-(1H-1,2,4-triazol-5-yl)phenyl)-3-(cyclohexylmethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

or,

(R)-6-(4-(1H-1,2,4-triazol-5-yl)phenyl)-3-(cyclohexylmethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

In some embodiments of compounds of formula (I), R¹ is substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl. In oneembodiment, R¹ is phenyl, pyridyl, pyrimidyl, benzimidazolyl, indolyl,indazolyl, 1H-pyrrolo[2,3-b]pyridyl, 1H-imidazo[4,5-b]pyridyl,1H-imidazo[4,5-b]pyridin-2(3H)-onyl, 3H-imidazo[4,5-b]pyridyl, orpyrazolyl, each optionally substituted. In some embodiments, R¹ isphenyl substituted with one or more substituents independently selectedfrom the group consisting of substituted or unsubstituted C₁₋₈ alkyl(for example, methyl), substituted or unsubstituted heterocyclyl (forexample, substituted or unsubstituted triazolyl or pyrazolyl), halogen(for example, fluorine), aminocarbonyl, cyano, hydroxyalkyl (forexample, hydroxypropyl), and hydroxy. In other embodiments, R¹ ispyridyl substituted with one or more substituents independently selectedfrom the group consisting of substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted heterocyclyl (for example, substituted orunsubstituted triazolyl), halogen, aminocarbonyl, cyano, hydroxyalkyl,—OR, and —NR₂, wherein each R is independently H, or a substituted orunsubstituted C₁₋₄ alkyl. In yet other embodiments, R¹ is1H-pyrrolo[2,3-b]pyridyl or benzimidazolyl, each optionally substitutedwith one or more substituents independently selected from the groupconsisting of substituted or unsubstituted C₁₋₈ alkyl, and —NR₂, whereineach R is independently H, or a substituted or unsubstituted C₁₋₄ alkyl.

In some embodiments of compounds of formula (I), R¹ is

wherein R is at each occurrence independently H, or a substituted orunsubstituted C₁₋₄ alkyl (for example, methyl); R′ is at each occurrenceindependently a substituted or unsubstituted C₁₋₄ alkyl, halogen (forexample, fluorine), cyano, —OR, or —NR₂; m is 0-3; and n is 0-3. It willbe understood by those skilled in the art that any of the substitutentsR′ may be attached to any suitable atom of any of the rings in the fusedring systems. It will also be understood by those skilled in the artthat the connecting bond of R¹ (designated by the bisecting wavy line)may be attached to any of the atoms in any of the rings in the fusedring systems.

In some embodiments of compounds of formula (I), R¹ is

wherein R is at each occurrence independently H, or a substituted orunsubstituted C₁₋₄ alkyl; R′ is at each occurrence independently asubstituted or unsubstituted C₁₋₄ alkyl, halogen, cyano, —OR, or —NR₂; mis 0-3; and n is 0-3.

In some embodiments of compounds of formula (I), R² is H, substituted orunsubstituted C₁₋₈ alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedC₁₋₄ alkyl-heterocyclyl, substituted or unsubstituted C₁₋₄ alkyl-aryl,or substituted or unsubstituted C₁₋₄ alkyl-cycloalkyl. For example, R²is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl,tert-butyl, n-pentyl, isopentyl, cyclopentyl, cyclohexyl,tetrahydrofuranyl, tetrahydropyranyl, (C₁₋₄ alkyl)-phenyl, (C₁₋₄alkyl)-cyclopropyl, (C₁₋₄ alkyl)-cyclobutyl, (C₁₋₄ alkyl)-cyclopentyl,(C₁₋₄ alkyl)-cyclohexyl, (C₁₋₄ alkyl)-pyrrolidyl, (C₁₋₄alkyl)-piperidyl, (C₁₋₄ alkyl)-piperazinyl, (C₁₋₄ alkyl)-morpholinyl,(C₁₋₄ alkyl)-tetrahydrofuranyl, or (C₁₋₄ alkyl)-tetrahydropyranyl, eachoptionally substituted.

In other embodiments, R² is H, C₁₋₄ alkyl, (C₁₋₄alkyl)(OR),

wherein R is at each occurrence independently H, or a substituted orunsubstituted C₁₋₄ alkyl (for example, methyl); R′ is at each occurrenceindependently H, —OR, cyano, or a substituted or unsubstituted C₁₋₄alkyl (for example, methyl); and p is 0-3.

In some such embodiments, R² is H, C₁₋₄ alkyl, (C₁₋₄alkyl)(OR),

wherein R is at each occurrence independently H, or a substituted orunsubstituted C₁₋₂ alkyl; R′ is at each occurrence independently H, —OR,cyano, or a substituted or unsubstituted C₁₋₂ alkyl; and p is 0-1.

In some other embodiments of compounds of formula (I), R² and one of R³and R⁴ together with the atoms to which they are attached form asubstituted or unsubstituted heterocyclyl. For example, in someembodiments, the compound of formula (I) is

wherein R is at each occurrence independently H, or a substituted orunsubstituted C₁₋₄ alkyl; R″ is H, OR, or a substituted or unsubstitutedC₁₋₄ alkyl; and R¹ is as defined herein.

In some embodiments of compounds of formula (I), R³ and R⁴ are both H.In others, one of R³ and R⁴ is H and the other is other than H. In stillothers, one of R³ and R⁴ is C₁₋₄ alkyl (for example, methyl) and theother is H. In still others, both of R³ and R⁴ are C₁₋₄ alkyl (forexample, methyl).

In some such embodiments described above, R¹ is substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl. Forexample, R¹ is phenyl, pyridyl, pyrimidyl, benzimidazolyl, indolyl,indazolyl, 1H-pyrrolo[2,3-b]pyridyl, 1H-imidazo[4,5-b]pyridyl,1H-imidazo[4,5-b]pyridin-2(3H)-onyl, 3H-imidazo[4,5-b]pyridyl, orpyrazolyl, each optionally substituted. In some embodiments, R¹ isphenyl substituted with one or more substituents independently selectedfrom the group consisting of substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted heterocyclyl, halogen, aminocarbonyl,cyano, hydroxyalkyl and hydroxy. In others, R¹ is pyridyl substitutedwith one or more substituents independently selected from the groupconsisting of cyano, substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted heterocyclyl, hydroxyalkyl, halogen,aminocarbonyl, —OR, and —NR₂, wherein each R is independently H, or asubstituted or unsubstituted C₁₋₄ alkyl. In others, R¹ is1H-pyrrolo[2,3-b]pyridyl or benzimidazolyl, optionally substituted withone or more substituents independently selected from the groupconsisting of substituted or unsubstituted C₁₋₈ alkyl, and —NR₂, whereinR is independently H, or a substituted or unsubstituted C₁₋₄ alkyl

In certain embodiments, the compounds of formula (I) have an R¹ groupset forth herein and an R² group set forth herein.

In some embodiments of compounds of formula (I), the compound at aconcentration of 10 μM inhibits mTOR, DNA-PK, or PI3K or a combinationthereof, by at least about 50%. Compounds of formula (I) may be shown tobe inhibitors of the kinases above in any suitable assay system, such asthose described in the Examples herein.

In some embodiments of compounds of formula (I), the compound is

-   6-(1H-pyrrolo[2,3-b]pyridin-3-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(4-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-4-((trans-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-4-((cis-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-((trans-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-4-((trans-4-hydroxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-((cis-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-((trans-4-hydroxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-(cis-4-hydroxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-((cis-4-hydroxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-4-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-(trans-4-hydroxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-4-((cis-4-hydroxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-(cis-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-isopropyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-4-(cis-4-hydroxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-4-(cis-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-4-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-ethyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-4-(trans-4-hydroxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-4-isopropyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   4-ethyl-6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(3-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(3-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-4-(cis-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(3-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-4-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   4-(2-methoxyethyl)-6-(4-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(3-(1H-1,2,4-triazol-5-yl)phenyl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   5-(8-(2-methoxyethyl)-6-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-4-methylpicolinamide;-   3-(6-oxo-8-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)benzamide;-   3-(6-oxo-8-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)benzonitrile;-   5-(8-(trans-4-methoxycyclohexyl)-6-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-4-methylpicolinamide;-   6-(1H-imidazo[4,5-b]pyradin-6-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(1H-indazol-6-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   4-((1R,3S)-3-methoxycyclopentyl)-6-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   4-((1S,3R)-3-methoxycyclopentyl)-6-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   4-((1R,3R)-3-methoxycyclopentyl)-6-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   4-((1S,3S)-3-methoxycyclopentyl)-6-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   4-ethyl-6-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(1H-pyrrolo[2,3-b]pyradin-5-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(1H-indol-6-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(1H-indol-5-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   4-(((1R,3S)-3-methoxycyclopentyl)methyl)-6-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   4-(((1S,3R)-3-methoxycyclopentyl)methyl)-6-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(3-fluoro-2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(3-fluoro-2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-4-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   3,3-dimethyl-6-(4-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(((1R,3S)-3-methoxycyclopentyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-((1S,3R)-3-methoxycyclopentyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-4(1S,3S)-3-methoxycyclopentyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(((1R,3R)-3-methoxycyclopentyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-((1S,3S)-3-methoxycyclopentyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(((1R,3R)-3-methoxycyclopentyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(((1R,3S)-3-methoxycyclopentyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-4(1S,3R)-3-methoxycyclopentyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(3-fluoro-4-(4H-1,2,4-triazol-3-yl)phenyl)-4-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(3-fluoro-4-(4H-1,2,4-triazol-3-yl)phenyl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7′-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-1′-((tetrahydro-2H-pyran-4-yl)methyl)-1′H-spiro[cyclopentane-1,2′-pyrazino[2,3-b]pyrazin]-3′(4′H)-one;-   7′-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-1′-((tetrahydro-2H-pyran-4-yl)methyl)-1′H-spiro[cyclobutane-1,2′-pyrazino[2,3-b]pyrazin]-3′(4′H)-one;-   4-(cyclopropylmethyl)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7′-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-1′H-spiro[cyclopentane-1,2′-pyrazino[2,3-b]pyrazin]-3′(4′H)-one;-   7′-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-1′H-spiro[cyclobutane-1,2′-pyrazino[2,3-b]pyrazin]-3′(4′H)-one;-   7′-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-1′H-spiro[cyclopropane-1,2′-pyrazino[2,3-b]pyrazin]-3′(4′H)-one;-   (R)-6-(4-(4H-1,2,4-triazol-3-yl)phenyl)-4-((tetrahydrofuran-2-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   (S)-6-(4-(4H-1,2,4-triazol-3-yl)phenyl)-4-((tetrahydrofuran-2-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(1H-indazol-5-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   4-(6-oxo-8-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)benzamide;-   4-(2-methoxyethyl)-3,3-dimethyl-6-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   4-ethyl-3,3-dimethyl-6-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   3,3-dimethyl-6-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   (R)-6-(6-(1-hydroxyethyl)pyridin-3-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   3,3-dimethyl-6-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(2-hydroxypropan-2-yl)-4-methylpyridin-3-yl)-4-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(2-hydroxypropan-2-yl)-4-methylpyridin-3-yl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   3,3-dimethyl-6-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   3,3-dimethyl-6-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(2-hydroxypropan-2-yl)-2-methylpyridin-3-yl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(2-hydroxypropan-2-yl)-2-methylpyridin-3-yl)-4-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   (S)-6-(6-(1-hydroxyethyl)pyridin-3-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   3,3-dimethyl-6-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,3-dimethyl-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(4-(2-hydroxypropan-2-yl)phenyl)-4-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(4-(2-hydroxypropan-2-yl)phenyl)-4-((trans-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   4-(cis-4-methoxycyclohexyl)-6-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   4-(trans-4-methoxycyclohexyl)-6-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(4-(2-hydroxypropan-2-yl)phenyl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   4-(2-methoxyethyl)-6-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   9-(6-(4H-1,2,4-triazol-3-yl)-3-pyridyl)-6,11,4a-trihydromorpholino[4,3-e]pyrazino[2,3-b]pyrazin-5-one;-   6-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   5-(8-(cis-4-methoxycyclohexyl)-6-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-6-methylpicolinonitrile;-   6-(6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   9-(4-(4H-1,2,4-triazol-3-yl)-2-methylphenyl)-3-(2-methoxyacetyl)-6,11,4a-trihydropiperazino[1,2-e]pyrazino[2,3-b]pyrazin-5-one;-   9-(4-(4H-1,2,4-triazol-3-yl)-2-methylphenyl)-6,11,4a-trihydropiperazino[1,2-e]pyrazino[2,3-b]pyrazin-5-one;-   9-(4-(4H-1,2,4-triazol-3-yl)-2-methylphenyl)-3-(2-methoxyethyl)-6,11,4a-trihydropiperazino[1,2-e]pyrazino[2,3-b]pyrazin-5-one;-   4-(cyclopentylmethyl)-6-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   9-(6-(4H-1,2,4-triazol-3-yl)-2-methyl-3-pyridyl)-6,11,4a-trihydromorpholino[4,3-e]pyrazino[2,3-b]pyrazin-5-one;-   4-(trans-4-hydroxycyclohexyl)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   4-(cis-4-hydroxycyclohexyl)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-((tetrahydrofuran-3-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   4-(cyclopentylmethyl)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-neopentyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-isobutyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   3-methyl-6-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(piperidin-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(2-(tetrahydro-2H-pyran-3-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   8-(4-(4H-1,2,4-triazol-3-yl)-2-methylphenyl)(3aS,2R)-2-methoxy-5,10,3a-trihydropyrazino[2,3-b]pyrrolidino[1,2-e]pyrazin-4-one;-   8-(4-(4H-1,2,4-triazol-3-yl)-2-methylphenyl)(2R,3aR)-2-methoxy-5,10,3a-trihydropyrazino[2,3-b]pyrrolidino[1,2-e]pyrazin-4-one;-   8-(4-(4H-1,2,4-triazol-3-yl)-2-methylphenyl)(2S,3aR)-2-methoxy-5,10,3a-trihydropyrazino[2,3-b]pyrrolidino[1,2-e]pyrazin-4-one;-   8-(4-(4H-1,2,4-triazol-3-yl)-2-methylphenyl)(2S,3aS)-2-methoxy-5,10,3a-trihydropyrazino[2,3-b]pyrrolidino[1,2-e]pyrazin-4-one;-   6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(3-methoxypropyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   (S)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-((tetrahydrofuran-2-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   (R)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-((tetrahydrofuran-2-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   9-(4-(4H-1,2,4-triazol-3-yl)-2-methylphenyl)-3-methyl-6,    11,4a-trihydropiperazino[1,2-e]pyrazino[2,3-b]pyrazin-5-one;-   9-(4-(4H-1,2,4-triazol-3-yl)phenyl)-6,11,4a-trihydromorpholino[4,3-e]pyrazino[2,3-b]pyrazin-5-one;-   9-(4-(4H-1,2,4-triazol-3-yl)-2-methylphenyl)-6,11,4a-trihydropiperidino[1,2-e]pyrazino[2,3-b]pyrazin-5-one;-   6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(cis-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(2-morpholinoethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-phenethyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   4-(cyclohexylmethyl)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-((trans-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-((cis-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   (R)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(tetrahydrofuran-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   (S)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(tetrahydrofuran-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   (S)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3-methyl-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   9-[6-(1-hydroxy-isopropyl)-3-pyridyl]-6,11,4a-trihydromorpholino[4,3-e]pyrazino[2,3-b]pyrazin-5-one;-   6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(2-amino-7-methyl-1H-benzo[d]imidazol-5-yl)-4-(3-(trifluoromethyl)benzyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(3-(trifluoromethyl)benzyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   9-(4-(4H-1,2,4-triazol-3-yl)-2-methylphenyl)-6,11,4a-trihydromorpholino[4,3-e]pyrazino[2,3-b]pyrazin-5-one;-   6-(4-methyl-2-(methylamino)-1H-benzo[d]imidazol-6-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   8-(4-(4H-1,2,4-triazol-3-yl)-2-methylphenyl)-5,10,3a-trihydropyrazino[2,3-b]pyrrolidino[1,2-e]pyrazin-4-one;-   6-(4-(4H-1,2,4-triazol-3-yl)phenyl)-4-ethyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(4-(4H-1,2,4-triazol-3-yl)phenyl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(4-(4H-1,2,4-triazol-3-yl)phenyl)-4-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(4-(4H-1,2,4-triazol-3-yl)phenyl)-4-(3-(trifluoromethyl)benzyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(4-methyl-1H-benzo[d]imidazol-6-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(4-(2-hydroxypropan-2-yl)phenyl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;    or-   6-(4-(1H-1,2,4-triazol-5-yl)phenyl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one.

Further provided herein are compounds having the following formula (II):

and pharmaceutically acceptable salts, clathrates, solvates,stereoisomers, tautomers, and prodrugs thereof, wherein:

R¹ is substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted aryl, substituted or unsubstituted cycloalkyl, substitutedor unsubstituted heterocyclyl, or substituted or unsubstitutedheterocyclylalkyl;

R² is H, substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted heterocyclylalkyl, substituted orunsubstituted aralkyl, or substituted or unsubstituted cycloalkylalkyl;

R³ is H, or a substituted or unsubstituted C₁₋₈ alkyl;

provided the compound of formula (II) is not7-(4-hydroxyphenyl)-1-(3-methoxybenzyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one,depicted below:

In some embodiments of compounds of formula (II), R¹ is substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl. Forexample, R¹ is phenyl, pyridyl, pyrimidyl, benzimidazolyl,1H-pyrrolo[2,3-b]pyridyl, indazolyl, indolyl, 1H-imidazo[4,5-b]pyridyl,1H-imidazo[4,5-b]pyridin-2(3H)-onyl, 3H-imidazo[4,5-b]pyridyl, orpyrazolyl, each optionally substituted. In some embodiments, R¹ isphenyl substituted with one or more substituents independently selectedfrom the group consisting of substituted or unsubstituted C₁₋₈ alkyl(for example, methyl), substituted or unsubstituted heterocyclyl (forexample, a substituted or unsubstituted triazolyl or pyrazolyl),aminocarbonyl, halogen (for example, fluorine), cyano, hydroxyalkyl andhydroxy. In other embodiments, R¹ is pyridyl substituted with one ormore substituents independently selected from the group consisting ofsubstituted or unsubstituted C₁₋₈ alkyl (for example, methyl),substituted or unsubstituted heterocyclyl (for example, a substituted orunsubstituted triazolyl), halogen, aminocarbonyl, cyano, hydroxyalkyl(for example, hydroxypropyl), —OR, and —NR₂, wherein each R isindependently H, or a substituted or unsubstituted C₁₋₄ alkyl. In someembodiments, R¹ is 1H-pyrrolo[2,3-b]pyridyl or benzimidazolyl,optionally substituted with one or more substituents independentlyselected from the group consisting of substituted or unsubstituted C₁₋₈alkyl, and —NR₂, wherein R is independently H, or a substituted orunsubstituted C₁₋₄ alkyl.

In some embodiments, R¹ is

wherein R is at each occurrence independently H, or a substituted orunsubstituted C₁₋₄ alkyl (for example, methyl); R′ is at each occurrenceindependently a substituted or unsubstituted C₁₋₄ alkyl (for example,methyl), halogen (for example, fluoro), cyano, —OR, or —NR₂; m is 0-3;and n is 0-3. It will be understood by those skilled in the art that anyof the substitutents R′ may be attached to any suitable atom of any ofthe rings in the fused ring systems.

In some embodiments of compounds of formula (II), R¹ is

wherein R is at each occurrence independently H, or a substituted orunsubstituted C₁₋₄ alkyl; R′ is at each occurrence independently asubstituted or unsubstituted C₁₋₄ alkyl, halogen, cyano, —OR or —NR₂; mis 0-3; and n is 0-3.

In some embodiments of compounds of formula (II), R² is H, substitutedor unsubstituted C₁₋₈ alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedC₁₋₄ alkyl-heterocyclyl, substituted or unsubstituted C₁₋₄ alkyl-aryl,or substituted or unsubstituted C₁₋₄ alkyl-cycloalkyl. For example, R²is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl,tert-butyl, n-pentyl, isopentyl, cyclopentyl, cyclohexyl,tetrahydrofuranyl, tetrahydropyranyl, (C₁₋₄ alkyl)-phenyl, (C₁₋₄alkyl)-cyclopropyl, (C₁₋₄ alkyl)-cyclobutyl, (C₁₋₄ alkyl)-cyclopentyl,(C₁₋₄ alkyl)-cyclohexyl, (C₁₋₄ alkyl)-pyrrolidyl, (C₁₋₄alkyl)-piperidyl, (C₁₋₄ alkyl)-piperazinyl, (C₁₋₄ alkyl)-morpholinyl,(C₁₋₄ alkyl)-tetrahydrofuranyl, or (C₁₋₄ alkyl)-tetrahydropyranyl, eachoptionally substituted.

In other embodiments, R² is H, C₁₋₄ alkyl, (C₁₋₄alkyl)(OR),

wherein R is at each occurrence independently H, or a substituted orunsubstituted C₁₋₄ alkyl (for example, methyl); R′ is at each occurrenceindependently H, —OR, cyano, or a substituted or unsubstituted C₁₋₄alkyl (for example, methyl); and p is 0-3.

In other embodiments of compounds of formula (II), R² is H, C₁₋₄ alkyl,(C₁₋₄alkyl)(OR),

wherein R is at each occurrence independently H, or a substituted orunsubstituted C₁₋₂ alkyl; R′ is at each occurrence independently H, —OR,cyano, or a substituted or unsubstituted C₁₋₂ alkyl; and p is 0-1.

In other embodiments of compounds of formula (II), R³ is H.

In some such embodiments described herein, R¹ is substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl. Forexample, R¹ is phenyl, pyridyl, pyrimidyl, benzimidazolyl,1H-pyrrolo[2,3-b]pyridyl, indazolyl, indolyl, 1H-imidazo[4,5-b]pyridine,pyridyl, 1H-imidazo[4,5-b]pyridin-2(3H)-onyl, 3H-imidazo[4,5-b]pyridyl,or pyrazolyl, each optionally substituted. In some embodiments, R¹ isphenyl substituted with one or more substituents independently selectedfrom the group consisting of substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted heterocyclyl, aminocarbonyl, halogen,cyano, hydroxyalkyl and hydroxy. In others, R¹ is pyridyl substitutedwith one or more substituents independently selected from the groupconsisting of C₁₋₈ alkyl, substituted or unsubstituted heterocyclyl,halogen, aminocarbonyl, cyano, hydroxyalkyl, —OR, and —NR₂, wherein eachR is independently H, or a substituted or unsubstituted C₁₋₄ alkyl. Instill others, R¹ is 1H-pyrrolo[2,3-b]pyridyl or benzimidazolyl,optionally substituted with one or more substituents independentlyselected from the group consisting of substituted or unsubstituted C₁₋₈alkyl, and —NR₂, wherein R is independently H, or a substituted orunsubstituted C₁₋₄ alkyl.

In certain embodiments, the compounds of formula (II) have an R¹ groupset forth herein and an R² group set forth herein.

In some embodiments of compounds of formula (II), the compound at aconcentration of 10 μM inhibits mTOR, DNA-PK, PI3K, or a combinationthereof by at least about 50%. Compounds of formula (II) may be shown tobe inhibitors of the kinases above in any suitable assay system, such asthose described in the Examples herein.

In some embodiments of compounds of formula (II), the compound is

-   7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-((trans-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(cis-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-((cis-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-ethyl-7-(1H-pyrrolo[3,2-b]pyridin-5-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-((cis-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(1H-benzo[d]imidazol-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-((trans-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-((trans-4-hydroxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(cis-4-hydroxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(cis-4-hydroxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-ethyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-((cis-4-hydroxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(1H-indol-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-((trans-4-hydroxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-((cis-4-hydroxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(trans-4-hydroxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-isopropyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(trans-4-hydroxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-isopropyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-ethyl-7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(2-hydroxypyridin-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-isopropyl-7-(4-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   5-(8-isopropyl-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-4-methylpicolinamide;-   7-(1H-indazol-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(2-aminopyrimidin-5-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(2-aminopyridin-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(methylamino)pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-hydroxypyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(4-(1H-pyrazol-3-yl)phenyl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(1H-indazol-4-yl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(1H-indazol-6-yl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(pyrimidin-5-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-methoxypyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-(2-methoxyethyl)-7-(1H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-ethyl-7-(1H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-ethyl-7-(1H-indazol-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(pyridin-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-aminopyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-methyl-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   2-(2-hydroxypropan-2-yl)-5-(8-(trans-4-methoxycyclohexyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)pyridine    1-oxide;-   4-methyl-5-(7-oxo-8-((tetrahydro-2H-pyran-4-yl)methyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)picolinamide;-   5-(8-((cis-4-methoxycyclohexyl)methyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-4-methylpicolinamide;-   7-(1H-pyrazol-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-(trans-4-methoxycyclohexyl)-7-(4-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   3-((7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-2-oxo-3,4-dihydropyrazino[2,3-b]pyrazin-1    (2H)-yl)methyl)benzonitrile;-   1-((trans-4-methoxycyclohexyl)methyl)-7-(4-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   3-(7-oxo-8-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)benzamide;-   5-(8-((trans-4-methoxycyclohexyl)methyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-4-methylpicolinamide;-   3-((7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-2-oxo-3,4-dihydropyrazino[2,3-b]pyrazin-1    (2H)-yl)methyl)benzonitrile;-   7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((1R,3R)-3-methoxycyclopentyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((1S,3R)-3-methoxycyclopentyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((1S,3S)-3-methoxycyclopentyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((1R,3S)-3-methoxycyclopentyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(1H-indazol-6-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(2-morpholinoethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-(trans-4-hydroxycyclohexyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-(cis-4-hydroxycyclohexyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(2-morpholinoethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-isopropyl-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(1H-imidazo[4,5-b]pyridin-6-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-((cis-4-methoxycyclohexyl)methyl)-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-(trans-4-hydroxycyclohexyl)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-(cis-4-hydroxycyclohexyl)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   4-(7-oxo-8-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)benzamide;-   7-(1H-indazol-5-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-((1S,3R)-3-methoxycyclopentyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-((1R,3R)-3-methoxycyclopentyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-((1R,3S)-3-methoxycyclopentyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-((1S,3S)-3-methoxycyclopentyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(1H-indol-5-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-ethyl-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(1H-indol-6-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(4-(2-hydroxypropan-2-yl)phenyl)-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-((trans-4-methoxycyclohexyl)methyl)-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((cis-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-(2-methoxyethyl)-7-(4-methyl-2-(methylamino)-1H-benzo[d]imidazol-6-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(7-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-(2-methoxyethyl)-7-(4-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-benzyl-7-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(3-fluoro-4-(4H-1,2,4-triazol-3-yl)phenyl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(3-fluoro-4-(4H-1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(3-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-(trans-4-methoxycyclohexyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(5-fluoro-2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(3-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-(2-methoxyethyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((trans-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-(cyclopentylmethyl)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(4-(2-hydroxypropan-2-yl)phenyl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   (S)-7-(6-(1-hydroxyethyl)pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   (R)-7-(6-(1-hydroxyethyl)pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(4-(2-hydroxypropan-2-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(4-(trifluoromethyl)benzyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(3-(trifluoromethyl)benzyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(3-methoxypropyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(4-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(4-methyl-2-(methylamino)-1H-benzo[d]imidazol-6-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(2-amino-4-methyl-1H-benzo[d]imidazol-6-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   (R)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3-methyl-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   (S)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3-methyl-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(2-amino-4-methyl-1H-benzo[d]imidazol-6-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(4-(1H-1,2,4-triazol-5-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-(1-hydroxypropan-2-yl)-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;    or-   1-(2-hydroxyethyl)-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one.

Representative Heteroaryl Compounds of formula (I) and (II) are setforth in Table 1.

4.3 Methods for Making Heteroaryl Compounds

The Heteroaryl Compounds can be made by one skilled in the art usingconventional organic syntheses and commercially available materials. Byway of example and not limitation, a Heteroaryl Compound can be preparedas outlined in Schemes 1-9 shown below, as well as in the examples setforth in Section 5.1. It should be noted that one skilled in the art canmodify the procedures set forth in the illustrative schemes and examplesto arrive at the desired product.

Synthesis of compounds of formula (I) is shown in Scheme 1. Startingfrom 5-bromopyrazin-2-amine A, the R¹ group can be introduced using theappropriate boronic acid or borate ester (R⁺ is H, or together with theboron atom and the atoms to which they are attached, form a cyclicboronate), palladium catalyst (such as, for example,dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane),solvent (such as dimethylformamide) and base (such as sodium carbonate)through a Suzuki coupling, or alternately with the appropriate stannane(R⁺⁺ is C₁₋₄ alkyl), palladium catalyst (such asdichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethaneor palladium(dba)₂/tri-o-tolylphosphine) and solvent (such asdimethylformamide with or without the addition of a base such astriethylamine) using Stille coupling methodology. Typical reactionconditions and reagents for Suzuki and Stille reactions can be foundherein (see also Rossi, et al, Synthesis 15:2419-2440 (2004), Buchwaldet al. Accounts of Chemical Research, 41: 1461-1473 (2008), Fu. Accountsof Chemical Research, 41: 1555-1564 (2008), and Echavarren et al. Angew.Chem. Int. Ed., 43: 4704-4734 (2004) and references therein). Theresulting R¹ amino pyrazine B can be brominated using NBS or otherstandard brominating conditions to afford the brominated intermediate C,which is then reacted with 2-bromoacetic anhydride to afford theacylated intermediate D. The R² substituent is introduced through amineaddition to D and subsequent ring closure, in the presence of an aminebase (such as, for example, triethyl amine) and heating in anappropriate solvent (such as acetonitrile) to afford the desiredproducts.

Alternatively as shown in Scheme 2,3,5-dibromopyrazin-2-amine E, istreated with 2-bromoacetic anhydride as above to provide intermediate F.As described above, the R² substituent is introduced through amineaddition to F and subsequent ring closure to afford intermediate G. TheR¹ group may then be introduced using the methods described above,namely by reaction with the appropriate boronic acid or borate ester, inthe presence of a palladium catalyst and base through a Suzuki coupling,or alternately with the appropriate stannane, in the presence of apalladium catalyst using Stille coupling methodology as described above,to afford the desired products.

In an another approach (Scheme 3), 3,5-dibromopyrazin-2-amine E, istreated with 2-chloroacetic anhydride followed by sodium iodide toprovide the iodo intermediate F2. Intermediate F2 is converted to thedesired products following the procedures outlined in Scheme 2 for F.

To afford analogs with substitution alpha to the carbonyl (Scheme 4),the appropriately substituted amino-protected amino acid H (P_(N) isamino protecting group such as Boc), is reacted with3,5-dibromopyrazin-2-amine in the presence of a coupling agent, such as,for example, 1,1′-carbonyldiimidazole. Deprotection conditions (forexample, when P_(N) is Boc, deprotection is achieved by, for example,treatment with TFA or HCl), followed by palladium catalyzed ring closure(using, for example, sodium bicarbonate, palladium(II) acetate and4,5-bis(diphenylphosphino)-9,9-dimethylxanthene) to afford intermediateI. As before, the R¹ group may be introduced using the appropriateboronic acid or borate ester, palladium catalyst, solvent and basethrough a Suzuki coupling, or alternately with the appropriate stannane,palladium catalyst and solvent using Stille coupling methodology(described above) to afford the desired products. This method may alsobe used to afford analogs where R² is hydrogen. Additionally, this routemay be used to afford compounds wherein R³ and R⁴, together with theatom to which they are both attached, form a spiro-cyclic ring, throughthe use of appropriate starting amino acids.

Analogs wherein R² and R³ together with the atoms to which they areattached form a ring (see Scheme 5) may be obtained similarly to thechemistry shown in Scheme 4, beginning with the appropriate cyclic aminoacid J.

To obtain the desired products, the reactivity of the coupling partnersmay be reversed. For example, as shown in Scheme 6, intermediate I maybe converted to the corresponding stannane K, through reaction with, forexample, hexamethylditin (R⁺⁺ is methyl) in the presence of a palladiumcatalyst (such as tetrakis(triphenylphosphine)-palladium) and the R¹group may be introduced using the appropriate halogen (such as bromide),and solvent using Stille coupling methodology as described above toafford the desired products. Alternatively, intermediate I may beconverted to the corresponding boronate ester K2, by reaction with4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) in thepresence of a palladium catalyst (such as1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane) and abase (such as potassium acetate) in a solvent such as dioxane. The R¹group may be introduced using the appropriate halogen (such as bromide),palladium catalyst and solvent using Suzuki coupling methodology asdescribed above, to afford the desired products.

Compounds of formula (II) may be obtained as shown in Scheme 7.Reductive amination of 3,5-dibromopyrazin-2-amine E with ethyl2-oxoacetate (in the presence of, for example, sodium borohydride as areducing agent) affords intermediate L. Alternatively,3,5-dibromopyrazin-2-amine E may be converted to intermediate L byreaction with ethyl 2-chloroacetate under basic conditions (using forexample, Cs₂CO₃). The R² substituent is introduced through amineaddition to L, in the presence of an amine base, such asdiisopropylethylamine, and heating in an appropriate solvent (such asDMSO) and subsequent acid catalyzed ring closure (using, for example,acetic acid) to afford intermediate M. Alternatively, the ring closureof the amine addition product L may proceed under basic catalyzedconditions, such as treatment with potassium t-butoxide in anappropriate solvent. As before, the R¹ group may be introduced using theappropriate boronic acid or borate ester, palladium catalyst, solventand base through a Suzuki coupling, or alternately with the appropriatestannane, palladium catalyst and solvent using Stille couplingmethodology (described above) to afford the desired products.

An alternative approach (Scheme 8) begins with reaction of2,6-dichloropyrazine N with the appropriate amino ester (R^(^) is C₁₋₃alkyl), followed by reductive dehalogenation with hydrogen and apalladium catalyst such as palladium hydroxide, a base such as potassiumcarbonate, in a solvent such as ethanol, and subsequent bromination byreaction with a brominating agent such as NBS to yield intermediate O.As above, the R² substituent is introduced through amine addition to Oand subsequent acid catalyzed ring closure to afford intermediate P. TheR¹ group may be introduced using the appropriate boronic acid or borateester, palladium catalyst, solvent and base through a Suzuki coupling,or alternately with the appropriate stannane, palladium catalyst andsolvent using Stille coupling methodology to afford the desired products(described above). This route also allows for the synthesis of analogswith R³ substitution alpha to the carbonyl group.

As before, to obtain the desired products, the reactivity of thecoupling partners may be reversed (Scheme 9). For example, intermediateP may be converted to the corresponding stannane Q, and the R¹ group maybe introduced using the appropriate halogen, palladium catalyst andsolvent using Stille coupling methodology as described above to affordthe desired products. Alternatively, intermediate P may be converted tothe corresponding boronate ester Q2, and the R¹ group may be introducedusing the appropriate halogen, palladium catalyst and solvent usingSuzuki coupling methodology as described above to afford the desiredproducts.

Provided herein are methods of preparing a compound of formula (I),

the method comprising contacting a compound of formula (III)

with R¹—Y in a solvent, in the presence of a palladium catalyst, whereinsaid contacting occurs under conditions suitable to provide a compoundof formula (I), wherein R¹, R², R³ and R⁴ are as defined herein, and

a) when X is halogen (for example Br, Cl, or I) then Y is B(OR⁺)₂ orSn(R⁺⁺)₃; or

b) when Y is halogen (for example Br, Cl, or I), then X is B(OR⁺)₂ orSn(R⁺⁺)₃;

wherein each R⁺ is independently hydrogen or substituted orunsubstituted C₁₋₃ alkyl, or each R⁺, together with the boron atom andthe atoms to which they are attached, form a cyclic boronate; and R⁺⁺ isa C₁₋₄ alkyl.

Typically the solvent is dimethylformamide, isopropanol, dioxane,toluene, dimethylacetamide, tetrahydrofuran, acetonitrile, isopropylacetate, dimethyl sulfoxide, acetone, methanol, methyl t-butyl ether ora combination thereof, with or without the presence of water, and thepalladium catalyst isdichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloro-methane), palladium(dba)₂/tri-o-tolylphosphine,dichloro[1,1′-bis(ditert-butylphosphino)ferrocene]palladium,dichlorobis(p-dimethylamino phenylditbutylphosphine)palladium(II),tetrakis(triphenylphosphine)palladium(0), or palladium (II)acetate/4,5-bis(diphenylphosphino)-9,9-dimethylxanthene. In someembodiments when X or Y is a halogen, the halogen is Br. In someembodiments when X or Y is B(OR⁺)₂, the contacting occurs in thepresence of a base such as sodium carbonate, triethyl amine,diisopropylethyl amine, piperidine, pyridine, cesium carbonate,potassium carbonate, potassium phosphate, or sodium hydroxide. In somesuch embodiments, B(OR⁺)₂ is B(OH)₂ or B(—OC(CH₃)₂C(CH₃)₂O—). In otherembodiments, when X or Y is Sn(R⁺⁺)₃ the contacting optionally occurs inthe presence of a base such as triethylamine, sodium carbonate,diisopropylethyl amine, piperidine, pyridine, cesium carbonate,potassium carbonate, potassium phosphate, or sodium hydroxide. In somesuch embodiments, R⁺⁺ is methyl or n-butyl.

Also provided are methods of preparing a compound of formula (III),

the method comprising contacting a compound of formula (IV)

with R²—NH₂ in a solvent, such as acetonitrile or tetrahydrofuran, inthe presence of a base, such as triethylamine or diisopropylethylamine,wherein said contacting occurs under conditions suitable to provide acompound of formula (III), wherein R² is as defined herein, R³ and R⁴are H, X is a halogen such as Br, Hal is a halogen such as Br, and Hal²is Br or I.

Also provided are methods of preparing a compound of formula (III),

the method comprising cyclizing a compound of formula (V)

in a solvent, such as acetonitrile, in the presence of a palladiumcatalyst, such as palladium(II)acetate, a ligand, such as4,5-bis-(diphenylphosphino)-9,9-dimethylxanthene, and a base, such assodium bicarbonate, wherein said cyclization occurs under conditionssuitable to provide a compound of formula (III), wherein R² is asdefined herein, R³ and R⁴ are as described herein, X is a halogen suchas Br, and Hal is a halogen such as Br.

Also provided are methods of preparing a compound of formula (II),

the method comprising contacting a compound of formula (VI)

with R¹—Y in a solvent, in the presence of a palladium catalyst, whereinsaid contacting occurs under conditions suitable to provide a compoundof formula (I), wherein R¹, R², and R³ are as defined herein, and

a) when X is halogen (for example Br, Cl, or I) then Y is B(OR⁺)₂ orSn(R⁺⁺)₃; or

b) when Y is halogen (for example Br, Cl, or I), then X is B(OR⁺)₂ orSn(R⁺⁺)₃;

wherein each R⁺ is independently hydrogen or substituted orunsubstituted C₁₋₃ alkyl, or each R⁺, together with the boron atom andthe atoms to which they are attached, form a cyclic boronate; and eachR⁺⁺ is a C₁₋₃ alkyl.

Typically the solvent is dimethylformamide, isopropanol, dioxane,toluene, dimethylacetamide, tetrahydrofuran, acetonitrile, isopropylacetate, dimethyl sulfoxide, acetone, methanol, methyl t-butyl ether ora combination thereof, with or without the presence of water, and thepalladium catalyst isdichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloro-methane), palladium(dba)₂/tri-o-tolylphosphine,dichloro[1,1′-bis(ditert-butylphosphino)ferrocene]palladium,dichlorobis(p-dimethylamino phenylditbutylphosphine)palladium(II),tetrakis(triphenylphosphine)palladium(0), or palladium (II)acetate/4,5-bis(diphenylphosphino)-9,9-dimethylxanthene. In someembodiments when X or Y is a halogen, the halogen is Br. In someembodiments when X or Y is B(OR⁺)₂, the contacting occurs in thepresence of a base such as sodium carbonate, triethyl amine,diisopropylethyl amine, piperidine, pyridine, cesium carbonate,potassium carbonate, potassium phosphate, or sodium hydroxide. In somesuch embodiments, B(OR⁺)₂ is B(OH)₂ or B(—OC(CH₃)₂C(CH₃)₂O—). In otherembodiments, when X or Y is Sn(R⁺⁺)₃ the contacting optionally occurs inthe presence of a base such as triethylamine, sodium carbonate,diisopropylethyl amine, piperidine, pyridine, cesium carbonate,potassium carbonate, potassium phosphate, or sodium hydroxide. In somesuch embodiments, R⁺⁺ is methyl or n-butyl.

Also provided are methods of preparing a compound of formula (VI),

the method comprising cyclizing a compound of formula (VII)

in the presence of a base, such as potassium butoxide, or an acid, suchas acetic acid, TFA, HCl, or phosphoric acid, wherein said cyclizationoccurs under conditions suitable to provide a compound of formula (VI),wherein R² and R³ are as defined herein, Hal is a halogen such as Br,and R is H or C₁₋₄ alkyl. Typically, the cyclization is performed in asolvent, such as, for example, methanol or water.

Also provided are methods of preparing a compound of formula (VII),

the method comprising contacting a compound of formula (VIII)

with R²—NH₂ in a solvent, such as dimethylsulfoxide orN-methylpyrrolidinone, optionally in the presence of a base, such astriethylamine or diisopropylethylamine, wherein said contacting occursunder conditions suitable to provide a compound of formula (VII),wherein R² and R³ are as defined herein, and Hal is a halogen such asBr.

Pharmaceutically acceptable salts of the Heteroaryl Compounds can beformed by conventional and known techniques, such as by reacting aHeteroaryl Compound with a suitable acid as disclosed above. Such saltsare typically formed in high yields at moderate temperatures, and oftenare prepared by merely isolating the compound from a suitable acidicwash in the final step of the synthesis. The salt-forming acid maydissolved in an appropriate organic solvent, or aqueous organic solvent,such as an alkanol, ketone or ester. On the other hand, if theHeteroaryl Compound is desired in the free base form, it may be isolatedfrom a basic final wash step, according to known techniques. Forexample, a typical technique for preparing hydrochloride salt is todissolve the free base in a suitable solvent, and dry the solutionthoroughly, as over molecular sieves, before bubbling hydrogen chloridegas through it.

4.4 Methods of Use

Heteroaryl Compounds described herein have utility as pharmaceuticals totreat or prevent disease in animals or humans. Further, HeteroarylCompounds described herein are active against kinases (e.g., proteinkinases), including those involved in cancer, inflammatory conditions,immunological conditions, neurodegenerative diseases, diabetes, obesity,neurological disorders, age-related diseases, and cardiovascularconditions. Without being limited by theory, it is thought theHeteroaryl Compounds are effective for treating and preventing saiddiseases and conditions due to their ability to modulate (e.g., inhibit)kinases which are involved in the etiology of these diseases andconditions. Accordingly, provided herein are many uses of the HeteroarylCompounds, including the treatment or prevention of those diseases setforth below. The methods provided herein comprise the administration ofan effective amount of one or more Heteroaryl Compounds to a patient inneed thereof. In some embodiments, the methods additionally compriseadministration of a second active agent as described herein.

Representative immunological conditions that Heteroaryl Compounds areuseful for treating or preventing include, but are not limited to,rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, multiplesclerosis, lupus, inflammatory bowel disease, ulcerative colitis,Crohn's disease, myasthenia gravis, Graves disease, encephalomyelitis,Type II diabetes, dermatomyositis, and transplant rejection (e.g. in thetreatment of recipients of e.g. heart, lung, combined heart-lung, liver,kidney, pancreatic, skin or corneal transplants; or graft-versus-hostdisease, such as following bone marrow transplantation).

Representative inflammatory conditions that Heteroaryl Compounds areuseful for treating or preventing include, but are not limited to,psoriasis, asthma and allergic rhinitis, bronchitis, chronic obstructivepulmonary disease, cystic fibrosis, inflammatory bowel disease,irritable bowel syndrome, Crohn's disease, mucous colitis, ulcerativecolitis, and obesity.

Representative cardiovascular diseases that Heteroaryl Compounds areuseful for treating or preventing include, but are not limited to,restenosis, Wolf-Parkinson-White Syndrome, stroke, myocardial infarctionor ischemic damage to the heart, lung, gut, kidney, liver, pancreas,spleen or brain.

Representative neurodegenerative diseases that Heteroaryl Compounds areuseful for treating or preventing include, but are not limited to,Huntington's disease, Alzheimer's disease, Parkinson's disease,dementias caused by tau mutations, spinocerebellar ataxia type 3, motorneuron disease caused by SOD1 mutations, neuronal ceroidlipofucinoses/Batten disease (pediatric neurodegene ration) andHIV-associated encephalitis.

Representative age-related diseases that Heteroaryl Compounds are usefulfor treating or preventing include but are not limited to cancer,obesity, type II diabetes mellitus, autoimmune disease, cardiovasculardiseases and neuronal degeneration.

In another embodiment, provided herein are methods for the treatment orprevention of fibrotic diseases and disorders. In a particularembodiment, provided herein are methods for the treatment or preventionof scleroderma, idiopathic pulmonary fibrosis, renal fibrosis, cysticfibrosis, myelofibrosis, hepatic fibrosis, steatofibrosis andsteatohepatitis.

Representative cancers that Heteroaryl Compounds are useful for treatingor preventing include, but are not limited to, cancers of the head,neck, eye, mouth, throat, esophagus, bronchus, larynx, pharynx, chest,bone, lung, colon, rectum, stomach, prostate, urinary bladder, uterine,cervix, breast, ovaries, testicles or other reproductive organs, skin,thyroid, blood, lymph nodes, kidney, liver, pancreas, and brain orcentral nervous system. Heteroaryl Compounds are also useful fortreating or preventing solid tumors and bloodborne tumors.

Particular cancers within the scope of the methods provided hereininclude those associated with the pathways involving mTOR, PI3K, or Aktkinases and mutants or isoforms thereof. Other cancers within the scopeof the methods provided herein include those associated with thepathways of the following kinases: PI3Kα, PI3Kβ, PI3Kδ, KDR, GSK3α,GSK3β, ATM, ATX, ATR, cFMS, and/or DNA-PK kinases and mutants orisoforms thereof. In some embodiments, the cancers associated withmTOR/PI3K/Akt pathways include solid and blood-borne tumors, forexample, multiple myeloma, mantle cell lymphoma, diffused large B-celllymphoma, acute myeloid lymphoma, follicular lymphoma, chroniclymphocytic leukemia; breast, lung, endometrial, ovarian, gastric,cervical, and prostate cancer; glioblastoma; renal carcinoma;hepatocellular carcinoma; colon carcinoma; neuroendocrine tumors; headand neck tumors; and sarcomas.

In a particular embodiment, provided herein are methods for thetreatment or prevention of a disease or disorder associated withactivation of mTOR signaling, including, but not limited to, tumorsyndromes resulting directly or indirectly from genetic defects in PTEN(Phosphatase and tensin homologue deleted on chromosome 10), TSC1(Tuberous sclerosis 1), TSC2 (Tuberous sclerosis 2), NF1 (Neurofibromin1), AMPK (AMP-dependent protein kinase STK11, serine/threonine kinase11), LKB1, VHL (von Hippel-Lindau disease) and PKD1 (polycystin-1).Without being limited by theory, it is thought that genetic defectsassociated with these proteins results in hyperactivation of themTOR/PI3K/Akt pathway. Some particular diseases which are treatable orpreventable through inhibition of the mTOR/PI3K/Akt pathway include, butare not limited to, Cowden's disease, Cowden syndrome, Cowden-likesyndrome, Bannayan-Zonana syndrome, Bannayan-Riley-Ruvalcaba syndrome,Lhermitte-Duclos disease, endometrial carcinoma, tuberous sclerosiscomplex, lymphangioleiomyomatosis, neurofibromatosis 1, Peutz-Jegherssyndrome, renal cell carcinoma, von Hippel-Lindau disease, Proteussyndrome, and polycystic kidney disease.

In a particular embodiment, provided herein are methods for thetreatment or prevention of a disease or disorder associated with mTOR,PI3K, Akt, and/or DNA-PK signaling. Particular diseases which aretreatable or preventable by inhibiting mTOR, PI3K, Akt and/or DNA-PKsignaling, include, but are not limited to, rheumatoid arthritis;rheumatoid spondylitis; osteoarthritis; gout; asthma, bronchitis;allergic rhinitis; chronic obstructive pulmonary disease; cysticfibrosis; inflammatory bowel disease; irritable bowel syndrome; mucouscolitis; ulcerative colitis; Crohn's disease; Huntington's disease;gastritis; esophagitis; hepatitis; pancreatitis; nephritis; multiplesclerosis; lupus erythematosus; atherosclerosis; restenosis followingangioplasty; left ventricular hypertrophy; myocardial infarction;stroke; ischemic damages of heart, lung, gut, kidney, liver, pancreas,spleen and brain; acute or chronic organ transplant rejection;preservation of the organ for transplantation; organ failure or loss oflimb (e.g., including, but not limited to, that resulting fromischemia-reperfusion injury, trauma, gross bodily injury, car accident,crush injury or transplant failure); graft versus host disease;endotoxin shock; multiple organ failure; psoriasis; burn from exposureto fire, chemicals or radiation; eczema; dermatitis; skin graft;ischemia; ischemic conditions associated with surgery or traumaticinjury (e.g., vehicle accident, gunshot wound or limb crush); epilepsy;Alzheimer's disease; Parkinson's disease; immunological response tobacterial or viral infection; cachexia; angiogenic and proliferativediseases (including retinitis pigmentosa), solid tumors, and cancers ofa variety of tissues such as colon, rectum, prostate, liver, lung,bronchus, pancreas, brain, head, neck, stomach, skin, kidney, cervix,blood, larynx, esophagus, mouth, pharynx, urinary bladder, ovary oruterine.

Also provided herein are methods for inhibiting a kinase in a cellexpressing said kinase, comprising contacting the cell with an effectiveamount of a Heteroaryl Compound as described herein. In one embodimentthe kinase is mTOR, DNA-PK, or PI3K or a combination thereof. In someembodiments, the cell is in a patient.

Also provided herein are methods for treating or preventing a conditiontreatable or preventable by inhibition of a kinase pathway, for example,the mTOR/PI3K/Akt and/or DNA-PK pathway, comprising administering to apatient in need thereof an effective amount of a Heteroaryl Compound asdescribed herein. In some embodiments, the conditions treatable orpreventable by inhibition of the mTOR/PI3K/Akt pathway include solid andblood-borne tumors, for example, multiple myeloma, mantle cell lymphoma,diffused large B-cell lymphoma, acute myeloid lymphoma, follicularlymphoma, chronic lymphocytic leukemia; breast, lung, endometrial,ovarian, gastric, cervical, and prostate cancer; glioblastoma; renalcarcinoma; hepatocellular carcinoma; colon carcinoma; neuroendocrinetumors; head and neck tumors; sarcomas; tumor syndromes resultingdirectly or indirectly from genetic defects in PTEN (Phosphatase andtensin homologue deleted on chromosome 10), TSC1 (Tuberous sclerosis 1),TSC2 (Tuberous sclerosis 2), NF1 (Neurofibromin 1), AMPK (AMP-dependentprotein kinase STK11, serine/threonine kinase 11), and LKB1, VHL (vonHippel-Lindau disease) and PKD1 (polycystin-1); Cowden's disease, Cowdensyndrome, Cowden-like syndrome, Bannayan-Zonana syndrome,Bannayan-Riley-Ruvalcaba syndrome, Lhermitte-Duclos disease, endometrialcarcinoma, tuberous sclerosis complex, lymphangioleiomyomatosis,neurofibromatosis 1, Peutz-Jeghers syndrome, renal cell carcinoma, vonHippel-Lindau disease, Proteus syndrome, and polycystic kidney disease;rheumatoid arthritis; rheumatoid spondylitis; osteoarthritis; gout;asthma, bronchitis; allergic rhinitis; chronic obstructive pulmonarydisease; cystic fibrosis; inflammatory bowel disease; irritable bowelsyndrome; mucous colitis; ulcerative colitis; Crohn's disease;Huntington's disease; gastritis; esophagitis; hepatitis; pancreatitis;nephritis; multiple sclerosis; lupus erythematosus; atherosclerosis;restenosis following angioplasty; left ventricular hypertrophy;myocardial infarction; stroke; ischemic damages of heart, lung, gut,kidney, liver, pancreas, spleen and brain; acute or chronic organtransplant rejection; preservation of the organ for transplantation;organ failure or loss of limb (e.g., including, but not limited to, thatresulting from ischemia-reperfusion injury, trauma, gross bodily injury,car accident, crush injury or transplant failure); graft versus hostdisease; endotoxin shock; multiple organ failure; psoriasis; burn fromexposure to fire, chemicals or radiation; eczema; dermatitis; skingraft; ischemia; ischemic conditions associated with surgery ortraumatic injury (e.g., vehicle accident, gunshot wound or limb crush);epilepsy; Alzheimer's disease; Parkinson's disease; immunologicalresponse to bacterial or viral infection; cachexia; angiogenic andproliferative diseases, including retinitis pigmentosa, solid tumors,and cancers of a variety of tissues such as colon, rectum, prostate,liver, lung, bronchus, pancreas, brain, head, neck, stomach, skin,kidney, cervix, blood, larynx, esophagus, mouth, pharynx, urinarybladder, ovary or uterine.

More particularly, cancers and related disorders that can be treated orprevented by methods and compositions provided herein include but arenot limited to the following: leukemias such as but not limited to,acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemiassuch as myeloblastic, promyelocytic, myelomonocytic, monocytic,erythroleukemia leukemias and myelodysplastic syndrome (or a symptomthereof such as anemia, thrombocytopenia, neutropenia, bicytopenia orpancytopenia), refractory anemia (RA), RA with ringed sideroblasts(RARS), RA with excess blasts (RAEB), RAEB in transformation (RAEB-T),preleukemia and chronic myelomonocytic leukemia (CMML), chronicleukemias such as but not limited to, chronic myelocytic (granulocytic)leukemia (CML), chronic lymphocytic leukemia (CLL), hairy cell leukemia;polycythemia vera; lymphomas such as but not limited to Hodgkin'sdisease, non-Hodgkin's disease; multiple myelomas such as but notlimited to smoldering multiple myeloma, nonsecretory myeloma,osteosclerotic myeloma, plasma cell leukemia, solitary plasmacytoma andextramedullary plasmacytoma; Waldenström's macroglobulinemia; monoclonalgammopathy of undetermined significance; benign monoclonal gammopathy;heavy chain disease; bone and connective tissue sarcomas such as but notlimited to bone sarcoma, osteosarcoma, chondrosarcoma, Ewing's sarcoma,malignant giant cell tumor, fibrosarcoma of bone, chordoma, periostealsarcoma, soft-tissue sarcomas, angiosarcoma (hemangiosarcoma),fibrosarcoma, Kaposi's sarcoma, leiomyosarcoma, liposarcoma,lymphangiosarcoma, metastatic cancers, neurilemmoma, rhabdomyosarcoma,synovial sarcoma; brain tumors such as but not limited to, glioma,astrocytoma, brain stem glioma, ependymoma, oligodendroglioma, nonglialtumor, acoustic neurinoma, craniopharyngioma, medulloblastoma,meningioma, pineocytoma, pineoblastoma, primary brain lymphoma; breastcancer, including, but not limited to, adenocarcinoma, lobular (smallcell) carcinoma, intraductal carcinoma, medullary breast cancer,mucinous breast cancer, tubular breast cancer, papillary breast cancer,primary cancers, Paget's disease, and inflammatory breast cancer;adrenal cancer such as but not limited to pheochromocytom andadrenocortical carcinoma; thyroid cancer such as but not limited topapillary or follicular thyroid cancer, medullary thyroid cancer andanaplastic thyroid cancer; pancreatic cancer such as but not limited to,insulinoma, gastrinoma, glucagonoma, vipoma, somatostatin-secretingtumor, and carcinoid or islet cell tumor; pituitary cancers such as butlimited to Cushing's disease, prolactin-secreting tumor, acromegaly, anddiabetes insipidus; eye cancers such as but not limited to ocularmelanoma such as iris melanoma, choroidal melanoma, and cilliary bodymelanoma, and retinoblastoma; vaginal cancers such as squamous cellcarcinoma, adenocarcinoma, and melanoma; vulvar cancer such as squamouscell carcinoma, melanoma, adenocarcinoma, basal cell carcinoma, sarcoma,and Paget's disease; cervical cancers such as but not limited to,squamous cell carcinoma, and adenocarcinoma; uterine cancers such as butnot limited to endometrial carcinoma and uterine sarcoma; ovariancancers such as but not limited to, ovarian epithelial carcinoma,borderline tumor, germ cell tumor, and stromal tumor; esophageal cancerssuch as but not limited to, squamous cancer, adenocarcinoma, adenoidcystic carcinoma, mucoepidermoid carcinoma, adenosquamous carcinoma,sarcoma, melanoma, plasmacytoma, verrucous carcinoma, and oat cell(small cell) carcinoma; stomach cancers such as but not limited to,adenocarcinoma, fungating (polypoid), ulcerating, superficial spreading,diffusely spreading, malignant lymphoma, liposarcoma, fibrosarcoma, andcarcinosarcoma; colon cancers; rectal cancers; liver cancers such as butnot limited to hepatocellular carcinoma and hepatoblastoma, gallbladdercancers such as adenocarcinoma; cholangiocarcinomas such as but notlimited to papillary, nodular, and diffuse; lung cancers such asnon-small cell lung cancer, squamous cell carcinoma (epidermoidcarcinoma), adenocarcinoma, large-cell carcinoma and small-cell lungcancer; testicular cancers such as but not limited to germinal tumor,seminoma, anaplastic, classic (typical), spermatocytic, nonseminoma,embryonal carcinoma, teratoma carcinoma, choriocarcinoma (yolk-sactumor), prostate cancers such as but not limited to, adenocarcinoma,leiomyosarcoma, and rhabdomyosarcoma; penal cancers; oral cancers suchas but not limited to squamous cell carcinoma; basal cancers; salivarygland cancers such as but not limited to adenocarcinoma, mucoepidermoidcarcinoma, and adenoidcystic carcinoma; pharynx cancers such as but notlimited to squamous cell cancer, and verrucous; skin cancers such as butnot limited to, basal cell carcinoma, squamous cell carcinoma andmelanoma, superficial spreading melanoma, nodular melanoma, lentigomalignant melanoma, acral lentiginous melanoma; kidney cancers such asbut not limited to renal cell cancer, adenocarcinoma, hypernephroma,fibrosarcoma, transitional cell cancer (renal pelvis and/or utero);Wilms' tumor; bladder cancers such as but not limited to transitionalcell carcinoma, squamous cell cancer, adenocarcinoma, carcinosarcoma. Inaddition, cancers include myxosarcoma, osteogenic sarcoma,endotheliosarcoma, lymphangio-endotheliosarcoma, mesothelioma,synovioma, hemangioblastoma, epithelial carcinoma, cystadenocarcinoma,bronchogenic carcinoma, sweat gland carcinoma, sebaceous glandcarcinoma, papillary carcinoma and papillary adenocarcinomas (for areview of such disorders, see Fishman et al., 1985, Medicine, 2d Ed.,J.B. Lippincott Co., Philadelphia and Murphy et al., 1997, InformedDecisions: The Complete Book of Cancer Diagnosis, Treatment, andRecovery, Viking Penguin, Penguin Books U.S.A., Inc., United States ofAmerica).

Accordingly, the methods and compositions provided herein are alsouseful in the treatment or prevention of a variety of cancers or otherabnormal proliferative diseases, including (but not limited to) thefollowing: carcinoma, including that of the bladder, breast, colon,kidney, liver, lung, ovary, pancreas, stomach, cervix, thyroid and skin;including squamous cell carcinoma; hematopoietic tumors of lymphoidlineage, including leukemia, acute lymphocytic leukemia, acutelymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Berkettslymphoma; hematopoietic tumors of myeloid lineage, including acute andchronic myelogenous leukemias and promyelocytic leukemia; tumors ofmesenchymal origin, including fibrosarcoma and rhabdomyoscarcoma; othertumors, including melanoma, seminoma, tetratocarcinoma, neuroblastomaand glioma; tumors of the central and peripheral nervous system,including astrocytoma, glioblastoma multiforme, neuroblastoma, glioma,and schwannomas; solid and bloodborne tumors; tumors of mesenchymalorigin, including fibrosarcoma, rhabdomyosarcoma, and osteosarcoma; andother tumors, including melanoma, xenoderma pigmentosum,keratoactanthoma, seminoma, thyroid follicular cancer andteratocarcinoma. It is also contemplated that cancers caused byaberrations in apoptosis would also be treated by the methods andcompositions disclosed herein. Such cancers may include but not belimited to follicular lymphomas, carcinomas with p53 mutations, hormonedependent tumors of the breast, prostate and ovary, and precancerouslesions such as familial adenomatous polyposis, juvenile polyposissyndrome, Birt-Hogg-Dubé syndrome (BHD), and myelodysplastic syndromes.In specific embodiments, malignancy or dysproliferative changes (such asmetaplasias and dysplasias), or hyperproliferative disorders, aretreated or prevented in the ovary, bladder, breast, colon, lung, skin,pancreas, kidney or uterus. In other specific embodiments, sarcoma,melanoma, or leukemia is treated or prevented.

In a particular embodiment, the methods and compositions provided hereinare also useful for treating, preventing or managing various types oflymphomas (i.e., a heterogenous group of neoplasms arising in thereticuloendothelial and lymphatic systems), such as Non-Hodgkin'slymphoma (NHL) (i.e., a malignant monoclonal proliferation of lymphoidcells in sites of the immune system, including lymph nodes, bone marrow,spleen, liver and gastrointestinal tract). NHLs that the HeteroarylCompounds are useful for treating or preventing include, but are notlimited to, mantle cell lymphoma, MCL, lymphocytic lymphoma ofintermediate differentiation, intermediate lymphocytic lymphoma, ILL,diffuse poorly differentiated lymphocytic lymphoma, PDL, centrocyticlymphoma, diffuse small-cleaved cell lymphoma, DSCCL, follicularlymphoma, and any type of the mantle cell lymphomas that can be seenunder the microscope (nodular, diffuse, blastic and mantle zonelymphoma).

In another embodiment, the methods and compositions provided herein arealso useful for administration to patients in need of treatment for amalignant disease (e.g., patients suffering from acute lymphocyticleukemia, acute myelogenous leukemia, chronic myelogenous leukemia,chronic lymphocytic leukemia, myelodysplastic syndrome (“preleukemia”),monosomy 7 syndrome, non-Hodgkin's lymphoma, neuroblastoma, braintumors, multiple myeloma, testicular germ cell tumors, breast cancer,lung cancer, ovarian cancer, melanoma, glioma, sarcoma or other solidtumors), as well as those in need of treatment of a non-malignantdisease (e.g., patients suffering from hematologic disorders, congenitalimmunodeficiencies, mucopolysaccharidoses, lipidoses, osteoporosis,Langerhan's cell histiocytosis, Lesch-Nyhan syndrome or glycogen storagediseases).

In another embodiment, provided herein are methods for the treatment ofmyeloproliferative disorders or myelodysplastic syndromes, comprisingadministering to a patient in need thereof an effective amount of aHeteroaryl Compound or a composition thereof. In certain embodiments,the myeloproliferative disorder is polycythemia rubra vera; primarythrombocythemia; chronic myelogenous leukemia; acute or chronicgranulocytic leukemia; acute or chronic myelomonocytic leukemia;myelofibro-erythroleukemia; or angiogenic myeloid metaplasia.

In another embodiment, provided herein are methods for the treatment ofcancer or tumors resistant to other kinase inhibitors such as imatinibmesylate (STI-571 or Gleevec™) treatment, comprising administering to apatient in need thereof an effective amount of a Heteroaryl Compound ora composition thereof. In a particular embodiment, provided herein aremethods for the treatment of leukemias, including, but not limited to,gastrointestinal stromal tumor (GIST), acute lymphocytic leukemia orchronic myelocytic leukemia resistant to imatinib mesylate (STI-571 orGleevec™) treatment, comprising administering to a patient in needthereof an effective amount of a Heteroaryl Compound or a compositionthereof.

In a specific embodiment, provided herein are methods for treating orpreventing leukemia (i.e., malignant neoplasms of the blood-formingtissues) including, but not limited to, chronic lymphocytic leukemia,chronic myelocytic leukemia, acute lymphoblastic leukemia, acutemyelogenous leukemia and acute myeloblastic leukemia. The leukemia canbe relapsed, refractory or resistant to conventional therapy. The term“relapsed” refers to a situation where patients who have had a remissionof leukemia after therapy have a return of leukemia cells in the marrowand a decrease in normal blood cells. The term “refractory or resistant”refers to a circumstance where patients, even after intensive treatment,have residual leukemia cells in their marrow.

The various types of the cancers are described in U.S. PatentApplication publication no. 2004/0029832, published Feb. 12, 2004, whichis incorporated herein in its entirety by reference (see, e.g., Section2.2. Types of Cancers). Specific cancers include, but are not limitedto, leukemias such as chronic lymphocytic leukemia, chronic myelocyticleukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, andacute myeloblastic leukemia; advanced malignancy, amyloidosis,neuroblastoma, meningioma, hemangiopericytoma, multiple brainmetastases, glioblastoma multiforms, glioblastoma, brain stem glioma,poor prognosis malignant brain tumor, malignant glioma, recurrentmalignant glioma, anaplastic astrocytoma, anaplastic oligodendroglioma,neuroendocrine tumor, rectal adenocarcinoma, Dukes C & D colorectalcancer, unresectable colorectal carcinoma, metastatic hepatocellularcarcinoma, Kaposi's sarcoma, karotype acute myeloblastic leukemia,Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-Cell lymphoma,cutaneous B-Cell lymphoma, diffuse large B-Cell lymphoma, low gradefollicular lymphoma, malignant melanoma, malignant mesothelioma,malignant pleural effusion mesothelioma syndrome, peritoneal carcinoma,papillary serous carcinoma, gynecologic sarcoma, soft tissue sarcoma,cutaneous vasculitis, Langerhans cell histiocytosis, leiomyosarcoma,fibrodysplasia ossificans progressive, hormone refractory prostatecancer, resected high-risk soft tissue sarcoma, unresectablehepatocellular carcinoma, Waldenstrom's macroglobulinemia, smolderingmyeloma, indolent myeloma, fallopian tube cancer, androgen independentprostate cancer, androgen dependent stage IV non-metastatic prostatecancer, hormone-insensitive prostate cancer, chemotherapy-insensitiveprostate cancer, papillary thyroid carcinoma, follicular thyroidcarcinoma, medullary thyroid carcinoma, and leiomyoma. In oneembodiment, the cancer is primary or metastatic. In another embodiment,the cancer is relapsed, refractory or resistance to chemotherapy orradiation; in particular, refractory to thalidomide.

Further provided herein are methods for treating patients who have beenpreviously treated for cancer, but are non-responsive to standardtherapies, as well as those who have not previously been treated. Alsoprovided herein are methods for treating patients regardless ofpatient's age, although some cancers are more common in certain agegroups. Still further provided herein are methods for treating patientswho have undergone surgery in an attempt to treat the cancer at issue,as well as those who have not. Because patients with cancer haveheterogenous clinical manifestations and varying clinical outcomes, thetreatment given to a patient may vary, depending on his/her prognosis.The skilled clinician will be able to readily determine without undueexperimentation specific secondary agents, types of surgery, and typesof non-drug based standard therapy that can be effectively used to treatan individual patient with cancer.

Further, provide herein are methods for the treatment or prevention ofdisorders such as pulmonary hypertension, Carney Complex, muscle wasting(atrophy, cachexia), myopathies such as Danon's disease, and bacterial,fungal, and viral infections (including M. tuberculosis, group Astreptococcus, HSV type I, and HIV infection).

A Heteroaryl Compound can be combined with other pharmacologicallyactive compounds (“second active agents”) in methods and compositionsdescribed herein. It is believed that certain combinations may work inthe treatment of particular types of diseases or disorders, andconditions and symptoms associated with such diseases or disorders. AHeteroaryl Compound can also work to alleviate adverse effectsassociated with certain second active agents, and vice versa.

One or more second active ingredients or agents can be used in themethods and compositions described herein. Second active agents can belarge molecules (e.g., proteins) or small molecules (e.g., syntheticinorganic, organometallic, or organic molecules).

Examples of large molecule second active agents include, but are notlimited to, hematopoietic growth factors, cytokines, and monoclonal andpolyclonal antibodies. Specific examples of the active agents areanti-CD40 monoclonal antibodies (such as, for example, SGN-40); histonedeacetylyase inhibitors (such as, for example, MGCD0103, SAHA and LAQ824); hypomethylating agents (such as Vidaza); IMiDs® brandImmunomodulatory products (such as thalidomide, lenalidomide andpomalidomide); heat-shock protein-90 inhibitors (such as, for example,17-AAG); insulin-like growth factor-1 receptor kinase inhibitors;vascular endothelial growth factor receptor kinase inhibitors (such as,for example, PTK787); insulin growth factor receptor inhibitors;lysophosphatidic acid acyltransrerase inhibitors; IkB kinase inhibitors;p38MAPK inhibitors; Pim kinase inhibitors (such as, for example,SGI-1776, or those disclosed in WO/2008/106692); EGFR inhibitors (suchas, for example, gefitinib and erlotinib HCL); HER-2 antibodies (suchas, for example, trastuzumab (Herceptin®) and pertuzumab (Omnitarg™), aswell as HER-2 kinase inhibitors (such as Lapatinib); VEGFR antibodies(such as, for example, bevacizumab (Avastin™)); VEGFR inhibitors (suchas, for example, flk-1 specific kinase inhibitors, SU5416 andptk787/zk222584); PI3K inhibitors (such as, for example, wortmannin);C-Met inhibitors (such as, for example, PHA-665752); antiestrogens (suchas, for example, Letrozole, Fulvestrant, tamoxifen); monoclonalantibodies (such as, for example, rituximab (Rituxan®), tositumomab(Bexxar®), edrecolomab (Panorex®) and G250); and anti-TNF-α antibodies.Examples of small molecule active agents include, but are not limitedto, small molecule anti-cancer agents and antibiotics (e.g.,clarithromycin).

Specific second active compounds that can be combined with a HeteroarylCompound vary depending on the specific indication to be treated,prevented or managed.

For instance, for the treatment, prevention or management of cancer,second active agents include, but are not limited to: anti-folates suchas Pemetrexed™; semaxanib; cyclosporin; etanercept; doxycycline;bortezomib; acivicin; aclarubicin; acodazole hydrochloride; acronine;adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate;amsacrine; anastrozole; anthramycin; asparaginase; asperlin;azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide;bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycinsulfate; brequinar sodium; bropirimine; busulfan; cactinomycin;calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicinhydrochloride; carzelesin; cedefingol; celecoxib; chlorambucil;cirolemycin; cisplatin; cladribine; crisnatol mesylate;cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicinhydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguaninemesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride;droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin;edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin;enpromate; epipropidine; epirubicin hydrochloride; erbulozole;esorubicin hydrochloride; estramustine; estramustine phosphate sodium;etanidazole; etoposide; etoposide phosphate; etoprine; fadrozolehydrochloride; fazarabine; fenretinide; floxuridine; fludarabinephosphate; fluorouracil; fluorocitabine; fosquidone; fostriecin sodium;gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicinhydrochloride; ifosfamide; ilmofosine; iproplatin; irinotecan;irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolideacetate; liarozole hydrochloride; lometrexol sodium; lomustine;losoxantrone hydrochloride; masoprocol; maytansine; mechlorethaminehydrochloride; megestrol acetate; melengestrol acetate; melphalan;menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine;meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin;mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolicacid; nocodazole; nogalamycin; ormaplatin; oxisuran; paclitaxel;pegaspargase; peliomycin; pentamustine; peplomycin sulfate;perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride;plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine;procarbazine hydrochloride; puromycin; puromycin hydrochloride;pyrazofurin; riboprine; safingol; safingol hydrochloride; semustine;simtrazene; sparfosate sodium; sparsomycin; spirogermaniumhydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin;sulofenur; talisomycin; tecogalan sodium; taxotere; tegafur;teloxantrone hydrochloride; temoporfin; teniposide; teroxirone;testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin;tirapazamine; toremifene citrate; trestolone acetate; triciribinephosphate; trimetrexate; trimetrexate glucuronate; triptorelin;tubulozole hydrochloride; uracil mustard; uredepa; vapreotide;verteporfin; vinblastine sulfate; vincristine sulfate; vindesine;vindesine sulfate; vinepidine sulfate; vinglycinate sulfate;vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;vinzolidine sulfate; vorozole; zeniplatin; zinostatin; and zorubicinhydrochloride.

Other second agents include, but are not limited to:20-epi-1,25-dihydroxyvitamin D3; 5-ethynyluracil; abiraterone;aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TKantagonists; altretamine; ambamustine; amidox; amifostine;aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole;andrographolide; angiogenesis inhibitors; antagonist D; antagonist G;antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen,prostatic carcinoma; antiestrogen; antineoplaston; antisenseoligonucleotides; aphidicolin glycinate; apoptosis gene modulators;apoptosis regulators; compounds targeting metabolism such as resveratol;apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine;atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3;azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol;batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine;beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid;bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine;bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane;buthionine sulfoximine; calcipotriol; calphostin C; camptothecinderivatives; capecitabine; carboxamide-amino-triazole;carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor;carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropinB; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost;cis-porphyrin; cladribine; clathromycin; clomifene analogues;clotrimazole; collismycin A; collismycin B; combretastatin A4;combretastatin analogue; conagenin; crambescidin 816; crisnatol;cryptophycin 8; cryptophycin A derivatives; curacin A;cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate;cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B;deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil;diaziquone; didemnin B; didox; diethylnorspermine;dihydro-5-azacytidine; 9-dihydrotaxol; dioxamycin; diphenylspiromustine; docetaxel; docosanol; dolasetron; doxifluridine;doxorubicin; droloxifene; dronabinol; duocarmycin SA; ebselen;ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur;epirubicin; epristeride; estramustine analogue; estrogen agonists;estrogen antagonists; etanidazole; etoposide phosphate; exemestane;fadrozole; fazarabine; fenretinide; filgrastim; finasteride;flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicinhydrochloride; forfenimex; formestane; fostriecin; fotemustine;gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam;heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid;idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imatinib(Gleevec®), imiquimod; immunostimulant peptides; insulin-like growthfactor-1 receptor inhibitor; interferon agonists; interferons;interleukins; iobenguane; iododoxorubicin; 4-ipomeanol; iroplact;irsogladine; isobengazole; isohomohalicondrin B; itasetron;jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide;leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole;leukemia inhibiting factor; leukocyte alpha interferon;leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole;linear polyamine analogue; lipophilic disaccharide peptide; lipophilicplatinum compounds; lissoclinamide 7; lobaplatin; lombricine;lometrexol; lonidamine; losoxantrone; loxoribine; lurtotecan; lutetiumtexaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A;marimastat; masoprocol; maspin; matrilysin inhibitors; matrixmetalloproteinase inhibitors; menogaril; merbarone; meterelin;methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine;mirimostim; mitoguazone; mitolactol; mitomycin analogues; mitonafide;mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene;molgramostim; Erbitux, human chorionic gonadotrophin; monophosphoryllipid A+myobacterium cell wall sk; mopidamol; mustard anticancer agent;mycaperoxide B; mycobacterial cell wall extract; myriaporone;N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin;nemorubicin; neridronic acid; nilutamide; nisamycin; nitric oxidemodulators; nitroxide antioxidant; nitrullyn; oblimersen (Genasense®);O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone;ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin;osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues;paclitaxel derivatives; palauamine; palmitoylrhizoxin; pamidronic acid;panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase;peldesine; pentosan polysulfate sodium; pentostatin; pentrozole;perflubron; perfosfamide; perillyl alcohol; phenazinomycin;phenylacetate; phosphatase inhibitors; picibanil; pilocarpinehydrochloride; pirarubicin; piritrexim; placetin A; placetin B;plasminogen activator inhibitor; platinum complex; platinum compounds;platinum-triamine complex; porfimer sodium; porfiromycin; prednisone;propyl bis-acridone; prostaglandin J2; proteasome inhibitors; proteinA-based immune modulator; protein kinase C inhibitor; protein kinase Cinhibitors, microalgal; protein tyrosine phosphatase inhibitors; purinenucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine;pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists;raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors;ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re186 etidronate; rhizoxin; ribozymes; RII retinamide; rohitukine;romurtide; roquinimex; rubiginone B1; ruboxyl; safingol; saintopin;SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine;senescence derived inhibitor 1; sense oligonucleotides; signaltransduction inhibitors; sizofiran; sobuzoxane; sodium borocaptate;sodium phenylacetate; solverol; somatomedin binding protein; sonermin;sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin1; squalamine; stipiamide; stromelysin inhibitors; sulfinosine;superactive vasoactive intestinal peptide antagonist; suradista;suramin; swainsonine; tallimustine; tamoxifen methiodide; tauromustine;tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomeraseinhibitors; temoporfin; teniposide; tetrachlorodecaoxide; tetrazomine;thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic;thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroidstimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocenebichloride; topsentin; toremifene; translation inhibitors; tretinoin;triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron;turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors;ubenimex; urogenital sinus-derived growth inhibitory factor; urokinasereceptor antagonists; vapreotide; variolin B; velaresol; veramine;verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole;zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.

Specific second active agents include, but are not limited to,2-methoxyestradiol, telomestatin, inducers of apoptosis in multiplemyeloma cells (such as, for example, TRAIL), bortezomib, statins,semaxanib, cyclosporin, etanercept, doxycycline, bortezomib, oblimersen(Genasense®), remicade, docetaxel, celecoxib, melphalan, dexamethasone(Decadron®), steroids, gemcitabine, cisplatinum, temozolomide,etoposide, cyclophosphamide, temodar, carboplatin, procarbazine,gliadel, tamoxifen, topotecan, methotrexate, Arisa®, taxol, taxotere,fluorouracil, leucovorin, irinotecan, xeloda, CPT-11, interferon alpha,pegylated interferon alpha (e.g., PEG INTRON-A), capecitabine,cisplatin, thiotepa, fludarabine, carboplatin, liposomal daunorubicin,cytarabine, doxetaxol, pacilitaxel, vinblastine, IL-2, GM-CSF,dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin,busulphan, prednisone, bisphosphonate, arsenic trioxide, vincristine,doxorubicin (Doxil®), paclitaxel, ganciclovir, adriamycin, estramustinesodium phosphate (Emcyt®), sulindac, and etoposide.

Similarly, examples of specific second agents according to theindications to be treated, prevented, or managed can be found in thefollowing references, all of which are incorporated herein in theirentireties: U.S. Pat. Nos. 5,635,517, 6,281,230, and 7,189,740; and U.S.patent application publication nos. 2004/0029832, 2004/0087546,2004/0091455, 2005/0100529, 2005/0214328, 2005/0239842, 2006/0122228,2006/0143344, 2006/0154880, and 2006/0188475.

Examples of additional second active agents include, but are not limitedto, conventional therapeutics used to treat or prevent pain such asantidepressants, anticonvulsants, antihypertensives, anxiolytics,calcium channel blockers, muscle relaxants, non-narcotic analgesics,opioid analgesics, anti-inflammatories, cox-2 inhibitors,immunomodulatory agents, alpha-adrenergic receptor agonists orantagonists, immunosuppressive agents, corticosteroids, hyperbaricoxygen, ketamine, other anesthetic agents, NMDA antagonists, and othertherapeutics found, for example, in the Physician's Desk Reference 2003.Specific examples include, but are not limited to, salicylic acidacetate (Aspirin®), celecoxib (Celebrex®), Enbrel®, ketamine, gabapentin(Neurontin®), phenyloin (Dilantin®), carbamazepine (Tegretol®),oxcarbazepine (Trileptal®), valproic acid (Depakene®), morphine sulfate,hydromorphone, prednisone, griseofulvin, penthonium, alendronate,dyphenhydramide, guanethidine, ketorolac (Acular®), thyrocalcitonin,dimethylsulfoxide (DMSO), clonidine (Catapress®), bretylium, ketanserin,reserpine, droperidol, atropine, phentolamine, bupivacaine, lidocaine,acetaminophen, nortriptyline (Pamelor®), amitriptyline (Elavil®),imipramine (Tofranil®), doxepin (Sinequan®), clomipramine (Anafranil®),fluoxetine (Prozac®), sertraline (Zoloft®), nefazodone (Serzone®),venlafaxine (Effexor®), trazodone (Desyrel®), bupropion (Wellbutrin®),mexiletine, nifedipine, propranolol, tramadol, lamotrigine, ziconotide,ketamine, dextromethorphan, benzodiazepines, baclofen, tizanidine andphenoxybenzamine.

Examples of additional second active agents include, but are not limitedto, a steroid, a light sensitizer, an integrin, an antioxidant, aninterferon, a xanthine derivative, a growth hormone, a neutrotrophicfactor, a regulator of neovascularization, an anti-VEGF antibody, aprostaglandin, an antibiotic, a phytoestrogen, an anti-inflammatorycompound or an antiangiogenesis compound, or a combination thereof.Specific examples include, but are not limited to, verteporfin,purlytin, an angiostatic steroid, rhuFab, interferon-2ÿ, pentoxifylline,tin etiopurpurin, motexafin lutetium,9-fluoro-11,21-dihydroxy-16,17-1-methylethylidinebis(oxy)pregna-1,4-diene-3,20-dione,latanoprost (see U.S. Pat. No. 6,225,348), tetracycline and itsderivatives, rifamycin and its derivatives, macrolides, metronidazole(U.S. Pat. Nos. 6,218,369 and 6,015,803), genistein, genistin, 6′-O-Malgenistin, 6′-O-Ac genistin, daidzein, daidzin, 6′-O-Mal daidzin, 6′-O-Acdaidzin, glycitein, glycitin, 6′-O-Mal glycitin, biochanin A,formononetin (U.S. Pat. No. 6,001,368), triamcinolone acetomide,dexamethasone (U.S. Pat. No. 5,770,589), thalidomide, glutathione (U.S.Pat. No. 5,632,984), basic fibroblast growth factor (bFGF), transforminggrowth factor b (TGF-b), brain-derived neurotrophic factor (BDNF),plasminogen activator factor type 2 (PAI-2), EYE101 (EyetechPharmaceuticals), LY333531 (Eli Lilly), Miravant, and RETISERT implant(Bausch & Lomb). All of the references cited above are incorporatedherein in their entireties by reference.

Examples of additional second active agents include, but are not limitedto, keratolytics, retinoids, α-hydroxy acids, antibiotics, collagen,botulinum toxin, interferon, and immunomodulatory agents. Specificexamples include, but are not limited to, 5-fluorouracil, masoprocol,trichloroacetic acid, salicylic acid, lactic acid, ammonium lactate,urea, tretinoin, isotretinoin, antibiotics, collagen, botulinum toxin,interferon, corticosteroid, transretinoic acid and collagens such ashuman placental collagen, animal placental collagen, Dermalogen,AlloDerm, Fascia, Cymetra, Autologen, Zyderm, Zyplast, Resoplast, andIsolagen.

Examples of additional second active agents include, but are not limitedto, anticoagulants, diuretics, cardiac glycosides, calcium channelblockers, vasodilators, prostacyclin analogues, endothelin antagonists,phosphodiesterase inhibitors (e.g., PDE V inhibitors), endopeptidaseinhibitors, lipid lowering agents, thromboxane inhibitors, and othertherapeutics known to reduce pulmonary artery pressure. Specificexamples include, but are not limited to, warfarin (Coumadin®), adiuretic, a cardiac glycoside, digoxin-oxygen, diltiazem, nifedipine, avasodilator such as prostacyclin (e.g., prostaglandin I2 (PGI2),epoprostenol (EPO, Floran®), treprostinil (Remodulin®), nitric oxide(NO), bosentan (Tracleer®), amlodipine, epoprostenol (Floran®),treprostinil (Remodulin®), prostacyclin, tadalafil (Clalis®),simvastatin (Zocor®), omapatrilat (Vanlev®), irbesartan (Avapro®),pravastatin (Pravachol®), digoxin, L-arginine, iloprost, betaprost, andsildenafil (Viagra®).

Examples of additional second active agents include, but are not limitedto, anthracycline, platinum, alkylating agent, oblimersen (Genasense®),cisplatinum, cyclophosphamide, temodar, carboplatin, procarbazine,gliadel, tamoxifen, topotecan, methotrexate, taxotere, irinotecan,capecitabine, cisplatin, thiotepa, fludarabine, carboplatin, liposomaldaunorubicin, cytarabine, doxetaxol, pacilitaxel, vinblastine, IL-2,GM-CSF, dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin,busulphan, prednisone, bisphosphonate, arsenic trioxide, vincristine,doxorubicin (Doxil®), paclitaxel, ganciclovir, adriamycin, bleomycin,hyaluronidase, mitomycin C, mepacrine, thiotepa, tetracycline andgemcitabine.

Examples of additional second active agents include, but are not limitedto, chloroquine, quinine, quinidine, pyrimethamine, sulfadiazine,doxycycline, clindamycin, mefloquine, halofantrine, primaquine,hydroxychloroquine, proguanil, atovaquone, azithromycin, suramin,pentamidine, melarsoprol, nifurtimox, benznidazole, amphotericin B,pentavalent antimony compounds (e.g., sodium stiboglucuronate),interfereon gamma, itraconazole, a combination of dead promastigotes andBCG, leucovorin, corticosteroids, sulfonamide, spiramycin, IgG(serology), trimethoprim, and sulfamethoxazole.

Examples of additional second active agents include, but are not limitedto: antibiotics (therapeutic or prophylactic) such as, but not limitedto, ampicillin, clarithromycin, tetracycline, penicillin,cephalosporins, streptomycin, kanamycin, and erythromycin; antiviralssuch as, but not limited to, amantadine, rimantadine, acyclovir, andribavirin; immunoglobulin; plasma; immunologic enhancing drugs such as,but not limited to, levami sole and isoprinosine; biologics such as, butnot limited to, gammaglobulin, transfer factor, interleukins, andinterferons; hormones such as, but not limited to, thymic; and otherimmunologic agents such as, but not limited to, B cell stimulators(e.g., BAFF/BlyS), cytokines (e.g., IL-2, IL-4, and IL-5), growthfactors (e.g., TGF-ÿ, antibodies (e.g., anti-CD40 and IgM),oligonucleotides containing unmethylated CpG motifs, and vaccines (e.g.,viral and tumor peptide vaccines).

Examples of additional second active agents include, but are not limitedto: a dopamine agonist or antagonist, such as, but not limited to,Levodopa, L-DOPA, cocaine, α-methyl-tyrosine, reserpine, tetrabenazine,benzotropine, pargyline, fenodolpam mesylate, cabergoline, pramipexoledihydrochloride, ropinorole, amantadine hydrochloride, selegilinehydrochloride, carbidopa, pergolide mesylate, Sinemet CR, and Symmetrel;a MAO inhibitor, such as, but not limited to, iproniazid, clorgyline,phenelzine and isocarboxazid; a COMT inhibitor, such as, but not limitedto, tolcapone and entacapone; a cholinesterase inhibitor, such as, butnot limited to, physostigmine saliclate, physostigmine sulfate,physostigmine bromide, meostigmine bromide, neostigmine methylsulfate,ambenonim chloride, edrophonium chloride, tacrine, pralidoxime chloride,obidoxime chloride, trimedoxime bromide, diacetyl monoxim, endrophonium,pyridostigmine, and demecarium; an anti-inflammatory agent, such as, butnot limited to, naproxen sodium, diclofenac sodium, diclofenacpotassium, celecoxib, oxaprozin, diflunisal, etodolac, meloxicam,ibuprofen, ketoprofen, nabumetone, refecoxib, methotrexate, leflunomide,sulfasalazine, gold salts, Rho-D Immune Globulin, mycophenylate mofetil,cyclosporine, azathioprine, tacrolimus, basiliximab, daclizumab,salicylic acid, acetylsalicylic acid, methyl salicylate, diflunisal,salsalate, olsalazine, sulfasalazine, acetaminophen, indomethacin,sulindac, mefenamic acid, meclofenamate sodium, tolmetin, ketorolac,dichlofenac, flurbinprofen, oxaprozin, piroxicam, meloxicam,ampiroxicam, droxicam, pivoxicam, tenoxicam, phenylbutazone,oxyphenbutazone, antipyrine, aminopyrine, apazone, zileuton,aurothioglucose, gold sodium thiomalate, auranofin, methotrexate,colchicine, allopurinol, probenecid, sulfinpyrazone and benzbromarone orbetamethasone and other glucocorticoids; and an antiemetic agent, suchas, but not limited to, metoclopromide, domperidone, prochlorperazine,promethazine, chlorpromazine, trimethobenzamide, ondansetron,granisetron, hydroxyzine, acetylleucine monoethanolamine, alizapride,azasetron, benzquinamide, bietanautine, bromopride, buclizine,clebopride, cyclizine, dimenhydrinate, diphenidol, dolasetron,meclizine, methallatal, metopimazine, nabilone, oxyperndyl, pipamazine,scopolamine, sulpiride, tetrahydrocannabinol, thiethylperazine,thioproperazine, tropisetron, and a mixture thereof.

Examples of additional second active agents include, but are not limitedto, immunomodulatory agents, immunosuppressive agents,antihypertensives, anticonvulsants, fibrinolytic agents, antiplateletagents, antipsychotics, antidepressants, benzodiazepines, buspirone,amantadine, and other known or conventional agents used in patients withCNS injury/damage and related syndromes. Specific examples include, butare not limited to: steroids (e.g., glucocorticoids, such as, but notlimited to, methylprednisolone, dexamethasone and betamethasone); ananti-inflammatory agent, including, but not limited to, naproxen sodium,diclofenac sodium, diclofenac potassium, celecoxib, oxaprozin,diflunisal, etodolac, meloxicam, ibuprofen, ketoprofen, nabumetone,refecoxib, methotrexate, leflunomide, sulfasalazine, gold salts, RHo-DImmune Globulin, mycophenylate mofetil, cyclosporine, azathioprine,tacrolimus, basiliximab, daclizumab, salicylic acid, acetylsalicylicacid, methyl salicylate, diflunisal, salsalate, olsalazine,sulfasalazine, acetaminophen, indomethacin, sulindac, mefenamic acid,meclofenamate sodium, tolmetin, ketorolac, dichlofenac, flurbinprofen,oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, pivoxicam,tenoxicam, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine,apazone, zileuton, aurothioglucose, gold sodium thiomalate, auranofin,methotrexate, colchicine, allopurinol, probenecid, sulfinpyrazone andbenzbromarone; a cAMP analog including, but not limited to, db-cAMP; anagent comprising a methylphenidate drug, which comprises1-threo-methylphenidate, d-threo-methylphenidate,dl-threo-methylphenidate, 1-erythro-methylphenidate,d-erythro-methylphenidate, dl-erythro-methylphenidate, and a mixturethereof; and a diuretic agent such as, but not limited to, mannitol,furosemide, glycerol, and urea.

Examples of additional second active agents include, but are not limitedto, a tricyclic antidepressant agent, a selective serotonin reuptakeinhibitor, an antiepileptic agent (gabapentin, pregabalin,carbamazepine, oxcarbazepine, levitiracetam, topiramate), anantiaryhthmic agent, a sodium channel blocking agent, a selectiveinflammatory mediator inhibitor, an opioid agent, a secondimmunomodulatory compound, a combination agent, and other known orconventional agents used in sleep therapy. Specific examples include,but are not limited to, Neurontin, oxycontin, morphine, topiramate,amitryptiline, nortryptiline, carbamazepine, Levodopa, L-DOPA, cocaine,α-methyl-tyrosine, reserpine, tetrabenazine, benzotropine, pargyline,fenodolpam mesylate, cabergoline, pramipexole dihydrochloride,ropinorole, amantadine hydrochloride, selegiline hydrochloride,carbidopa, pergolide mesylate, Sinemet CR, Symmetrel, iproniazid,clorgyline, phenelzine, isocarboxazid, tolcapone, entacapone,physostigmine saliclate, physostigmine sulfate, physostigmine bromide,meostigmine bromide, neostigmine methylsulfate, ambenonim chloride,edrophonium chloride, tacrine, pralidoxime chloride, obidoxime chloride,trimedoxime bromide, diacetyl monoxim, endrophonium, pyridostigmine,demecarium, naproxen sodium, diclofenac sodium, diclofenac potassium,celecoxib, sulindac, oxaprozin, diflunisal, etodolac, meloxicam,ibuprofen, ketoprofen, nabumetone, refecoxib, methotrexate, leflunomide,sulfasalazine, gold salts, RHo-D Immune Globulin, mycophenylate mofetil,cyclosporine, azathioprine, tacrolimus, basiliximab, daclizumab,salicylic acid, acetylsalicylic acid, methyl salicylate, diflunisal,salsalate, olsalazine, sulfasalazine, acetaminophen, indomethacin,sulindac, mefenamic acid, meclofenamate sodium, tolmetin, ketorolac,dichlofenac, flurbinprofen, oxaprozin, piroxicam, meloxicam,ampiroxicam, droxicam, pivoxicam, tenoxicam, phenylbutazone,oxyphenbutazone, antipyrine, aminopyrine, apazone, zileuton,aurothioglucose, gold sodium thiomalate, auranofin, methotrexate,colchicine, allopurinol, probenecid, sulfinpyrazone, benzbromarone,betamethasone and other glucocorticoids, metoclopromide, domperidone,prochlorperazine, promethazine, chlorpromazine, trimethobenzamide,ondansetron, granisetron, hydroxyzine, acetylleucine monoethanolamine,alizapride, azasetron, benzquinamide, bietanautine, bromopride,buclizine, clebopride, cyclizine, dimenhydrinate, diphenidol,dolasetron, meclizine, methallatal, metopimazine, nabilone, oxyperndyl,pipamazine, scopolamine, sulpiride, tetrahydrocannabinol,thiethylperazine, thioproperazine, tropisetron, and a mixture thereof.

Examples of additional second active agents include, but are not limitedto: interleukins, such as IL-2 (including recombinant IL-II (“rIL2”) andcanarypox IL-2), IL-10, IL-12, and IL-18; interferons, such asinterferon alfa-2a, interferon alfa-2b, interferon alfa-n1, interferonalfa-n3, interferon beta-I a, and interferon gamma-I b; and G-CSF;hydroxyurea; butyrates or butyrate derivatives; nitrous oxide; HEMOXIN™(NIPRISAN™; see U.S. Pat. No. 5,800,819); Gardos channel antagonistssuch as clotrimazole and triaryl methane derivatives; Deferoxamine;protein C; and transfusions of blood, or of a blood substitute such asHemospan™ or Hemospan™ PS (Sangart).

Administration of a Heteroaryl Compound and a second active agent to apatient can occur simultaneously or sequentially by the same ordifferent routes of administration. The suitability of a particularroute of administration employed for a particular active agent willdepend on the active agent itself (e.g., whether it can be administeredorally without decomposing prior to entering the blood stream) and thedisease being treated. A preferred route of administration forHeteroaryl Compounds is oral. Preferred routes of administration for thesecond active agents or ingredients of the invention are known to thoseof ordinary skill in the art. See, e.g., Physicians' Desk Reference,1755-1760 (56th ed., 2002).

In one embodiment, the second active agent is administered intravenouslyor subcutaneously and once or twice daily in an amount of from about 1to about 1000 mg, from about 5 to about 500 mg, from about 10 to about350 mg, or from about 50 to about 200 mg. The specific amount of thesecond active agent will depend on the specific agent used, the type ofdisease being treated or managed, the severity and stage of disease, andthe amount(s) of a Heteroaryl Compound and any optional additionalactive agents concurrently administered to the patient.

Further provided herein are methods of reducing, treating and/orpreventing adverse or undesired effects associated with conventionaltherapy including, but not limited to, surgery, chemotherapy, radiationtherapy, hormonal therapy, biological therapy and immunotherapy.Heteroaryl Compounds and other active ingredients can be administered toa patient prior to, during, or after the occurrence of the adverseeffect associated with conventional therapy.

4.5 Pharmaceutical Compositions and Routes of Administration

Provided herein are compositions comprising an effective amount of aHeteroaryl Compound and compositions comprising an effective amount of aHeteroaryl Compound and a pharmaceutically acceptable carrier orvehicle. In some embodiments, the pharmaceutical composition describedherein are suitable for oral, parenteral, mucosal, transdermal ortopical administration.

The Heteroaryl Compounds can be administered to a patient orally orparenterally in the conventional form of preparations, such as capsules,microcapsules, tablets, granules, powder, troches, pills, suppositories,injections, suspensions and syrups. Suitable formulations can beprepared by methods commonly employed using conventional, organic orinorganic additives, such as an excipient (e.g., sucrose, starch,mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphateor calcium carbonate), a binder (e.g., cellulose, methylcellulose,hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone,gelatin, gum arabic, polyethyleneglycol, sucrose or starch), adisintegrator (e.g., starch, carboxymethylcellulose,hydroxypropylstarch, low substituted hydroxypropylcellulose, sodiumbicarbonate, calcium phosphate or calcium citrate), a lubricant (e.g.,magnesium stearate, light anhydrous silicic acid, talc or sodium laurylsulfate), a flavoring agent (e.g., citric acid, menthol, glycine ororange powder), a preservative (e.g., sodium benzoate, sodium bisulfite,methylparaben or propylparaben), a stabilizer (e.g., citric acid, sodiumcitrate or acetic acid), a suspending agent (e.g., methylcellulose,polyvinyl pyrroliclone or aluminum stearate), a dispersing agent (e.g.,hydroxypropylmethylcellulose), a diluent (e.g., water), and base wax(e.g., cocoa butter, white petrolatum or polyethylene glycol). Theeffective amount of the Heteroaryl Compound in the pharmaceuticalcomposition may be at a level that will exercise the desired effect; forexample, about 0.005 mg/kg of a patient's body weight to about 10 mg/kgof a patient's body weight in unit dosage for both oral and parenteraladministration.

The dose of a Heteroaryl Compound to be administered to a patient israther widely variable and can be patient to the judgment of ahealth-care practitioner. In general, the Heteroaryl Compounds can beadministered one to four times a day in a dose of about 0.005 mg/kg of apatient's body weight to about 10 mg/kg of a patient's body weight in apatient, but the above dosage may be properly varied depending on theage, body weight and medical condition of the patient and the type ofadministration. In one embodiment, the dose is about 0.01 mg/kg of apatient's body weight to about 5 mg/kg of a patient's body weight, about0.05 mg/kg of a patient's body weight to about 1 mg/kg of a patient'sbody weight, about 0.1 mg/kg of a patient's body weight to about 0.75mg/kg of a patient's body weight or about 0.25 mg/kg of a patient's bodyweight to about 0.5 mg/kg of a patient's body weight. In one embodiment,one dose is given per day. In any given case, the amount of theHeteroaryl Compound administered will depend on such factors as thesolubility of the active component, the formulation used and the routeof administration.

In another embodiment, provided herein are methods for the treatment orprevention of a disease or disorder comprising the administration ofabout 0.375 mg/day to about 750 mg/day, about 0.75 mg/day to about 375mg/day, about 3.75 mg/day to about 75 mg/day, about 7.5 mg/day to about55 mg/day or about 18 mg/day to about 37 mg/day of a Heteroaryl Compoundto a patient in need thereof.

In another embodiment, provided herein are methods for the treatment orprevention of a disease or disorder comprising the administration ofabout 1 mg/day to about 1200 mg/day, about 10 mg/day to about 1200mg/day, about 100 mg/day to about 1200 mg/day, about 400 mg/day to about1200 mg/day, about 600 mg/day to about 1200 mg/day, about 400 mg/day toabout 800 mg/day or about 600 mg/day to about 800 mg/day of a HeteroarylCompound to a patient in need thereof. In a particular embodiment, themethods disclosed herein comprise the administration of 400 mg/day, 600mg/day or 800 mg/day of a Heteroaryl Compound to a patient in needthereof.

In another embodiment, provided herein are unit dosage formulations thatcomprise between about 1 mg and about 2000 mg, about 1 mg and 200 mg,about 35 mg and about 1400 mg, about 125 mg and about 1000 mg, about 250mg and about 1000 mg, or about 500 mg and about 1000 mg of a HeteroarylCompound.

In a particular embodiment, provided herein are unit dosage formulationcomprising about 100 mg or 400 mg of a Heteroaryl Compound.

In another embodiment, provided herein are unit dosage formulations thatcomprise 1 mg, 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 35 mg, 50 mg,70 mg, 100 mg, 125 mg, 140 mg, 175 mg, 200 mg, 250 mg, 280 mg, 350 mg,500 mg, 560 mg, 700 mg, 750 mg, 1000 mg or 1400 mg of a HeteroarylCompound.

A Heteroaryl Compound can be administered once, twice, three, four ormore times daily.

A Heteroaryl Compound can be administered orally for reasons ofconvenience. In one embodiment, when administered orally, a HeteroarylCompound is administered with a meal and water. In another embodiment,the Heteroaryl Compound is dispersed in water or juice (e.g., applejuice or orange juice) and administered orally as a suspension. Inanother embodiment, when administered orally, a Heteroaryl Compound isadministered in a fasted state.

The Heteroaryl Compound can also be administered intradermally,intramuscularly, intraperitoneally, percutaneously, intravenously,subcutaneously, intranasally, epidurally, sublingually, intracerebrally,intravaginally, transdermally, rectally, mucosally, by inhalation, ortopically to the ears, nose, eyes, or skin. The mode of administrationis left to the discretion of the health-care practitioner, and candepend in-part upon the site of the medical condition.

In one embodiment, provided herein are capsules containing a HeteroarylCompound without an additional carrier, excipient or vehicle.

In another embodiment, provided herein are compositions comprising aneffective amount of a Heteroaryl Compound and a pharmaceuticallyacceptable carrier or vehicle, wherein a pharmaceutically acceptablecarrier or vehicle can comprise an excipient, diluent, or a mixturethereof. In one embodiment, the composition is a pharmaceuticalcomposition.

The compositions can be in the form of tablets, chewable tablets,capsules, solutions, parenteral solutions, troches, suppositories andsuspensions and the like. Compositions can be formulated to contain adaily dose, or a convenient fraction of a daily dose, in a dosage unit,which may be a single tablet or capsule or convenient volume of aliquid. In one embodiment, the solutions are prepared from water-solublesalts, such as the hydrochloride salt. In general, all of thecompositions are prepared according to known methods in pharmaceuticalchemistry. Capsules can be prepared by mixing a Heteroaryl Compound witha suitable carrier or diluent and filling the proper amount of themixture in capsules. The usual carriers and diluents include, but arenot limited to, inert powdered substances such as starch of manydifferent kinds, powdered cellulose, especially crystalline andmicrocrystalline cellulose, sugars such as fructose, mannitol andsucrose, grain flours and similar edible powders.

Tablets can be prepared by direct compression, by wet granulation, or bydry granulation. Their formulations usually incorporate diluents,binders, lubricants and disintegrators as well as the compound. Typicaldiluents include, for example, various types of starch, lactose,mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such assodium chloride and powdered sugar. Powdered cellulose derivatives arealso useful. In one embodiment, the pharmaceutical composition islactose-free. Typical tablet binders are substances such as starch,gelatin and sugars such as lactose, fructose, glucose and the like.Natural and synthetic gums are also convenient, including acacia,alginates, methylcellulose, polyvinylpyrrolidine and the like.Polyethylene glycol, ethylcellulose and waxes can also serve as binders.

A lubricant might be necessary in a tablet formulation to prevent thetablet and punches from sticking in the die. The lubricant can be chosenfrom such slippery solids as talc, magnesium and calcium stearate,stearic acid and hydrogenated vegetable oils. Tablet disintegrators aresubstances that swell when wetted to break up the tablet and release thecompound. They include starches, clays, celluloses, algins and gums.More particularly, corn and potato starches, methylcellulose, agar,bentonite, wood cellulose, powdered natural sponge, cation-exchangeresins, alginic acid, guar gum, citrus pulp and carboxymethyl cellulose,for example, can be used as well as sodium lauryl sulfate. Tablets canbe coated with sugar as a flavor and sealant, or with film-formingprotecting agents to modify the dissolution properties of the tablet.The compositions can also be formulated as chewable tablets, forexample, by using substances such as mannitol in the formulation.

When it is desired to administer a Heteroaryl Compound as a suppository,typical bases can be used. Cocoa butter is a traditional suppositorybase, which can be modified by addition of waxes to raise its meltingpoint slightly. Water-miscible suppository bases comprising,particularly, polyethylene glycols of various molecular weights are inwide use.

The effect of the Heteroaryl Compound can be delayed or prolonged byproper formulation. For example, a slowly soluble pellet of theHeteroaryl Compound can be prepared and incorporated in a tablet orcapsule, or as a slow-release implantable device. The technique alsoincludes making pellets of several different dissolution rates andfilling capsules with a mixture of the pellets. Tablets or capsules canbe coated with a film that resists dissolution for a predictable periodof time. Even the parenteral preparations can be made long-acting, bydissolving or suspending the Heteroaryl Compound in oily or emulsifiedvehicles that allow it to disperse slowly in the serum.

5. EXAMPLES

Chem-4D Draw (ChemInnovation Software, Inc., San Diego, Calif.) orChemDraw Ultra (Cambridgesoft, Cambridge, Mass.) was used to generatenames for chemical structures.

The following abbreviations were used in descriptions and examples:

AmPhos: p-dimethylamino phenylditbutylphosphine

Boc: tert-Butoxycarbonyl

dba: dibenzylidene acetone

DMSO: Dimethylsulfoxide

ESI: Electronspray ionization

HPLC: High performance liquid chromatography

mp: Melting point

MS: Mass spectrometry

NBS: N-Bromosuccinimide

NMR: Nuclear magnetic resonance

TFA: Trifluoroacetic acid

TLC: Thin layer chromatography

MTBE: methyl tert-butyl ether

The following Examples are presented by way of illustration, notlimitation.

5.1 SYNTHETIC EXAMPLES Example 17-(2-Amino-4-methyl-1H-benzo[d]imidazol-6-yl)-1-((tetrahydro-2H-pyran-4-yl)Methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

A. Ethyl 2-(6-chloropyrazin-2-ylamino)acetate

To 2,6-dichloropyrazine (50 g, 336 mmol) and ethyl 2-aminoacetate (34.6g, 336 mmol) was added triethylamine (140 mL, 1007 mmol) andacetonitrile (350 mL). The reaction was heated at 80° C. for 3 d.Precipitated triethylamine salts were removed by filtration and washedwith ethyl acetate and hexane (1:1) multiple times. The filtrate andwash solvent were combined and concentrated. The resulting white-yellowprecipitate was filtered and washed with 20% ethyl acetate in hexane toafford an off-white solid. The filtrate was subjected to the sameprocess to give an additional batch of off-yellow solid. The batcheswere combined to afford the title compound (35.5 g, 164 mmol, 49%yield). MS (ESI) m/z 216.1 [M+1]⁺.

B. Ethyl 2-(pyrazin-2-ylamino)acetate

Ethyl 2-(6-chloropyrazin-2-ylamino)acetate (23.6 g, 109 mmol) wasdissolved in non-denatured ethanol (250 mL) and potassium carbonate(15.13 g, 109 mmol) was added. The reaction was put under nitrogen andpalladium hydroxide (3.84 g, 5.47 mmol) was added. The reaction wasstirred under an atmosphere of hydrogen for 18 h. Additional palladiumhydroxide (3.84 g, 5.47 mmol) was added and the reaction was chargedwith additional hydrogen and allowed to stir overnight. The reaction wasfiltered through Celite and the solvent was removed under reducedpressure to afford the title compound (15.13 g, 84 mmol, 76% yield). MS(ESI) m/z 182.3 [M+1]⁺.

C. Ethyl 2-(3,5-dibromopyrazin-2-ylamino)acetate

Ethyl 2-(pyrazin-2-ylamino)acetate (7.6 g, 41.9 mmol) was dissolved indimethylsulfoxide (80 mL) and water (4.00 mL) and cooled to 0° C.N-Bromosuccinimide (18.66 g, 105 mmol) was added slowly over 15 min andthe reaction was allowed to warm to rt and stir for 48 h. An additional1.5 equiv N-bromosuccinimide was added and allowed to stir overnight.The reaction mixture was poured into ice water (200 mL) and extractedwith ethyl acetate (150 mL). The aqueous layer was neutralized withsodium carbonate slowly, until pH˜7 and extracted with ethyl acetate(3×150 mL). The organic layers were pooled, washed with brine, driedover magnesium sulfate, filtered and concentrated under reducedpressure. The residue was triturated with 25-33% ethyl acetate in hexaneand the resulting precipitate was filtered to give a yellow solid. Theremaining brown residue was purified using Biotage silica gelchromatography (0-60% ethyl acetate in hexane) to give another batch ofoff-yellow solid. The two batches were combined to afford 24 g of thetitle compound (24 g, 71 mmol, 75% yield). MS (ESI) m/z 338.1 [M]⁺,340.1 [M+2]⁺, 342.1 [M+4]⁺.

D. Ethyl2-(5-bromo-3-((tetrahydro-2H-pyran-4-yl)methylamino)pyrazin-2-ylamino)acetate

Ethyl 2-(3,5-dibromopyrazin-2-ylamino)acetate (2.00 g, 5.90 mmol),(tetrahydro-2H-pyran-4-yl)methanamine (0.713 g, 6.19 mmol),N,N-diisopropylethylamine (3.08 mL, 17.70 mmol) and dimethylsulfoxide (4mL) were combined in a microwave vial with a stirbar and heated in aBiotage Emrys Optimizer microwave reactor at 150° C. for 1 h. Theresulting mixture was transferred to a round bottom flask with methanol.The methanol and N,N-diisopropylethylamine were removed under reducedpressure and the residue purified using Biotage flash chromatography(5-100% ethyl acetate in hexane). Fractions containing the desiredproduct were combined in a separatory funnel and washed twice with waterand once with brine. The organics were dried over magnesium sulfate,filtered and concentrated under reduced pressure. The residue was driedunder high vacuum at 50° C. to give impure desired product (1.578 g) asan amber waxy solid which was taken on to the next step without furtherpurification. MS (ESI) m/z 373.4 [M]⁺, 375.4 [M+2]⁺.

E.7-Bromo-1-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

A stirred solution of ethyl2-(5-bromo-3-((tetrahydro-2H-pyran-4-yl)methylamino)pyrazin-2-ylamino)acetate(1.474 g, 3.95 mmol) in acetic acid (13 mL) in a sealed vessel washeated at 120° C. in an oil bath for 2 h. The acetic acid was removedunder reduced pressure. The residue was partitioned between ethylacetate and saturated aqueous sodium bicarbonate, shaken and the layersseparated. The water layer was extracted twice with ethyl acetate. Thecombined organics were dried over magnesium sulfate, filtered andconcentrated under reduced pressure. The residue was taken up indichloromethane and hexane and the resulting solids collected by vacuumfiltration. The solids were washed with hexane and dried under vacuum togive the desired product (0.879 g, 2.688 mmol, 68% yield) as a purplesolid. MS (ESI) m/z 327.1 [M]⁺, 329.0 [M+2]⁺.

F.2-Methyl-6-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

4-Bromo-2-methyl-6-nitroaniline (5 g, 21.64 mmol),bis(pinacolato)diboron (5.50 g, 21.64 mmol), potassium acetate (6.37 g,64.9 mmol) and N,N-dimethylformamide (100 mL) were combined and degassedunder vacuum. Palladium acetate (0.243 g, 1.082 mmol) was added and thesystem was degassed again. The reaction was heated to 90° C. for 2 h.The reaction was extracted with water and dichloromethane. The organiclayer was dried over anhydrous magnesium sulfate, filtered andconcentrated. The residue was purified by silica gel columnchromatography (0-30% ethyl acetate in hexanes) to give a yellow solid(5.3 g, 19.0 mmol, 88% yield). MS (ESI) m/z 279.0 [M+1]⁺.

G.3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene-1,2-diamine

A solution of2-Methyl-6-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline(5.3 g, 19.06 mmol) in methanol (50 mL) was purged with nitrogen gas.Palladium on carbon (10% by wt, 50 mg) was added and the reactionmixture was stirred under a hydrogen balloon for 16 h. The reaction wasfiltered through Celite and the filter cake was rinsed with methanol.The filtrate was concentrated and the resulting material was purified bysilica gel column chromatography (0-100% ethyl acetate in hexanes) togive a dark oil. The oil was triturated with 10% ether in hexanes togive a tan colored solid (4.2 g, 16.9 mmol, 89% yield). MS (ESI) m/z248.9 [M+1]⁺.

H.7-(3,4-Diamino-5-methylphenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene-1,2-diamine(0.523 g, 2.109 mmol),7-bromo-1-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one(0.600 g, 1.834 mmol),[1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (0.150 g, 0.183 mmol), sodium carbonate (1Min water, 5.50 mmol), 1,4-dioxane (4.1 mL) and isopropanol (1.4 mL) werecombined in a sealable vessel with a stirbar. The system was purged withnitrogen. The resulting mixture was sealed, stirred vigorously andheated at 100° C. for 3.5 h. The resulting mixture was diluted with 20%methanol in dichloromethane and all volatiles removed under reducedpressure. The residue was taken up in 20% methanol in dichloromethaneand concentrated under reduced pressure with silica gel. The residue waspurified using flash chromatography (1-10% methanol in dichloromethane)to give the desired product (0.669 g, 1.818 mmol, 99% yield) as a brownsolid. MS (ESI) m/z 369.1 [M+1]⁺.

I.7-(2-Amino-4-methyl-1H-benzo[d]imidazol-6-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

Cyanogen bromide (0.059 g, 0.556 mmol) in N,N-dimethylformamide (0.5 mL)was added to a stirred solution of7-(3,4-diamino-5-methylphenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one(0.195 g, 0.529 mmol) in N,N-dimethylformamide (3 mL) at 0° C. Theresulting dark brown mixture was capped and stirred at room temperaturefor 16 h. The resulting mixture was diluted with methanol, filtered andpurified using reverse-phase preparatory HPLC (5-50% acetonitrile+0.1%TFA in water+0.1% TFA, over 30 min). Fractions containing the desiredproduct were combined and most of the solvent removed under reducedpressure. The residue was loaded onto a Strata X-C ion exchange columnfrom Phenomenex. The column was washed successively with water,acetonitrile, methanol and 5% ammonium hydroxide in methanol. Theproduct eluted with the 5% ammonium hydroxide in methanol eluent and wasconcentrated under reduced pressure and dried under high vacuum at 50°C. to give the desired product (0.130 g, 0.331 mmol, 62% yield) as anorange solid. ¹H NMR (400 MHz, D₂O and DMSO-d₆) δ (ppm) 8.13 (s, 1H),7.56 (s, 1H), 7.36 (s, 1H), 4.18 (s, 2H), 4.03 (d, J=6.64 Hz, 2H),3.84-3.90 (m, 2H), 3.24 (t, J=11.32 Hz, 2H), 2.40 (s, 3H), 2.04-2.19 (m,1H), 1.59 (d, J=12.10 Hz, 2H), 1.25-1.41 (m, 2H); MS (ESI) m/z 394.2[M+1]⁺.

Example 23,3-Dimethyl-6-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

A. 3-(4-Bromo-3-methylphenyl)-4H-1,2,4-triazole

4-Bromo-3-methylbenzonitrile (10.0 g, 51.0 mmol) was dissolved inethanol (200 mL) with stirring and cooled to 0° C. under nitrogen.Hydrogen chloride gas was bubbled into the reaction mixture for 20 min.The resulting reaction mixture was capped and stirred while slowlywarming to room temperature for 5.5 h. Solvent was removed under reducedpressure and the residue dried under vacuum to give 13.86 g of anoff-white solid. The off-white solid, formic hydrazide (4.48 g, 74.6mmol), triethylamine (28.0 mL, 199 mmol) and ethanol (90 mL) werecombined in a sealed tube and heated, with stirring, at 90° C. for 6.5h. All the solvent was removed under reduced pressure and the resultingresidue partitioned between ethyl acetate and water. The layers wereseparated and the organics washed with brine, dried over magnesiumsulfate, filtered and concentrated under reduced pressure. The residuewas dissolved in hot ethyl acetate (13 mL), capped and let stand at roomtemperature overnight. The solvent was decanted away from the solids atthe bottom of the flask. The solids were washed with ethyl acetate anddiethyl ether and dried under vacuum at 45° C. to give the desiredproduct (7.47 g, 31.4 mmol, 63% yield) as a light yellow solid. MS (ESI)m/z 238.2 [M]⁺, 240.3 [M+2]⁺.

B.3-(4-Bromo-3-methylphenyl)-4-(tetrahydro-2H-pyran-2-yl)-4H-1,2,4-triazole

3-(4-Bromo-3-methylphenyl)-4H-1,2,4-triazole (2.00 g, 8.40 mmol) wasdissolved in tetrahydrofuran (10 mL) at room temperature with stirringunder nitrogen. 3,4-Dihydro-2H-pyran (3.80 mL, 42.0 mmol) andmethanesulfonic acid (0.027 mL, 0.42 mmol) were added and the resultingmixture heated at 50° C. under a reflux condenser under nitrogen for 20h. The resulting mixture was cooled to room temperature, diluted withethyl acetate and washed with saturated aqueous sodium bicarbonate andbrine. The organics were dried over magnesium sulfate, filtered andconcentrated under reduced pressure. Flash chromatography (10-30-50%ethyl acetate in hexanes) gave the desired product (2.64 g, 8.22 mmol,98% yield) as a yellow oil. MS (ESI) m/z 322 [M]⁺, 324 [M+2]⁺.

C.3-(3-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(tetrahydro-2H-pyran-2-yl)-4H-1,2,4-triazole

3-(4-Bromo-3-methylphenyl)-4-(tetrahydro-2H-pyran-2-yl)-4H-1,2,4-triazole(2.294 g, 7.12 mmol), bis(pinacolato)diboron (1.898 g, 7.48 mmol),[1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (291 mg, 0.36 mmol), potassium acetate (2.096g, 21.4 mmol) and dimethyl sulfoxide (15 mL) were combined in a roundbottom flask and stirred. The atmosphere in the flask was removed undervacuum and replaced with nitrogen three times. The resulting mixture washeated at 90° C. under nitrogen for 4 h. The resulting mixture wasdiluted with ethyl acetate and filtered through Celite. The filter cakewas washed thoroughly with ethyl acetate. The filtrate was washed twicewith water, once with brine, dried over magnesium sulfate, filtered andconcentrated under reduced pressure. Flash chromatography (30-50% ethylacetate in hexanes) gave a waxy semi-solid which was triturated withhexane at 45° C. The resulting solids were dried under vacuum to givethe desired product (2.10 g, 5.69 mmol, 80% yield) as a pink powder. MS(ESI) m/z 370 [M+1]⁺.

D. tert-Butyl1-(3,5-dibromopyrazin-2-ylamino)-2-methyl-1-oxopropan-2-ylcarbamate

1,1′-Carbonyldiimidazole (2.63 g, 16.24 mmol) was added to a stirredsolution of 2-(tert-butoxycarbonylamino)-2-methylpropanoic acid (3.00 g,14.76 mmol) in N,N-dimethylformamide (4 mL) and dichloromethane (8 mL)at room temperature. The resulting clear colorless mixture was stirredat room temperature under nitrogen for 3 h. N,N-Diisopropylethylamine(3.86 mL, 22.14 mmol) was added followed by 3,5-dibromopyrazin-2-amine(5.60 g, 22.14 mmol). The resulting mixture was heated at 50° C. under areflux condenser under nitrogen for 71 h. Dichloromethane was removedunder reduced pressure. The residue was diluted with ethyl acetate andwashed with water. The water layer was extracted with ethyl acetate. Thecombined organics were washed with brine, dried over magnesium sulfate,filtered and concentrated under reduced pressure. The residue wastriturated with 30% ethyl acetate in hexane and solids collected byvacuum filtration. The filtrate was concentrated under reduced pressureand purified using flash chromatography (5-50% ethyl acetate in hexane).Fractions containing the desired product were combined with the solidsobtained by filtration and concentrated under reduced pressure. Theresidue was dried under high vacuum to give the desired product (2.38 g,5.43 mmol, 37% yield) as an off-white solid. MS (ESI) m/z 439.3 [M+1]⁺,461.1 [M+Na]⁺.

E.N-(3,5-Dibromopyrazin-2-yl)-2-methyl-2-(2-(tetrahydro-2H-pyran-4-yl)ethylamino)propanamidetrifluoroacetate

TFA (3.66 mL, 47.5 mmol) was added to a stirred mixture of tert-butyl1-(3,5-dibromopyrazin-2-ylamino)-2-methyl-1-oxopropan-2-ylcarbamate(1.04 g, 2.374 mmol) in dichloromethane (20 mL). The resulting clearyellow solution was stirred at room temperature for 3 h. All volatileswere removed under reduced pressure and the residue dried under highvacuum to give a yellow semi-solid. MS (ESI) m/z 339.1 [M+1]⁺. Sodiumsulfate (1.686 g, 11.87 mmol) was added followed by2-(tetrahydro-2H-pyran-4-yl)acetaldehyde (0.396 g, 3.09 mmol) and1,2-dichloroethane (20 mL). The resulting mixture was stirred vigorouslyand heated at 80° C. under a reflux condenser under nitrogen for 2.5 h.More 2-(tetrahydro-2H-pyran-4-yl)acetaldehyde (0.100 g, 0.780 mmol) andsodium sulfate (1.00 g, 7.04 mmol) were added and heating at 80° C.continued for another 2 h. The resulting yellow solution was removed bypipette from the solid sodium sulfate into a dry 250 mL round bottomflask equipped with a stirbar. The resulting mixture was stirredvigorously and cooled to 0° C. under nitrogen. Sodiumtriacetoxyborohydride (0.553 g, 2.61 mmol) was added slowly. Theresulting mixture was stirred vigorously at 0° C. under nitrogen for 30min. The cold bath was removed and the resulting mixture stirred at roomtemperature under nitrogen for 2 h. The mixture was cooled to 0° C. andmore sodium triacetoxyborohydride (0.250 g, 1.180 mmol) was added. Thecold bath was removed and the resulting mixture stirred at roomtemperature under nitrogen for 1.5 h. More sodium triacetoxyborohydride(0.055 g, 0.260 mmol) was added. The resulting mixture was stirredvigorously at room temperature under nitrogen for 1 h and then stirredovernight at 0° C. The resulting mixture was diluted with methanol andthe volatiles removed under reduced pressure. The residue was taken upin methanol, filtered and purified using reverse-phase preparatory HPLC(10-40% acetonitrile+0.1% TFA in water+0.1% TFA, over 30 min). Fractionscontaining the desired product were combined and the solvent removedunder reduced pressure. The residue was dried under vacuum to give thedesired product (0.890 g, 1.978 mmol, 67% yield) as a slightly yellowfoam-solid. MS (ESI) m/z 451.3 [M+1]⁺.

F.6-Bromo-3,3-dimethyl-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

N-(3,5-Dibromopyrazin-2-yl)-2-methyl-2-(2-(tetrahydro-2H-pyran-4-yl)ethylamino)propanamidetrifluoroacetate (0.856 g, 1.517 mmol), N,N-diisopropylethylamine (1.321mL, 7.59 mmol) and 1,4-dioxane (25 mL) were combined in a sealablevessel with a stirbar. The system was purged with nitrogen and theresulting mixture was sealed, stirred vigorously and heated at 110° C.for 2.5 h. The reaction mixture was concentrated under reduced pressureand purified using flash chromatography (5-50% ethyl acetate in hexane)to give the desired product (0.394 g, 1.068 mmol, 70% yield) as a whitesolid. MS (ESI) m/z 369.4 [M]⁺, 371.3 [M+2]⁺.

G.3,3-Dimethyl-6-(2-methyl-4-(4-(tetrahydro-2H-pyran-2-yl)-4H-1,2,4-triazol-3-yl)phenyl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

3-(3-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(tetrahydro-2H-pyran-2-yl)-4H-1,2,4-triazole(1 equiv),6-bromo-3,3-dimethyl-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one(1 equiv), [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II),complex with dichloromethane (1:1) (0.1 equiv), 1 M sodium carbonate inwater (3 equiv), 1,4-dioxane and isopropanol were combined and thesystem was purged with nitrogen. The resulting mixture was stirredvigorously and heated at 100° C. for 1.5 h. The resulting mixture wascooled to room temperature, diluted with methanol and the volatilesremoved under reduced pressure. The residue was partitioned betweendichloromethane and water, shaken and the layers separated. The waterlayer was extracted with dichloromethane. The combined organics weredried over magnesium sulfate, filtered and concentrated under reducedpressure. The residue was purified using flash chromatography (20-100%ethyl acetate in hexane followed by 0-10% methanol in dichloromethane)to give the desired product in 97% yield. MS (ESI) m/z 532.7 [M+1]⁺.

H.3,3-Dimethyl-6-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

6 N Hydrochloric acid in water was added to a stirred mixture of3,3-dimethyl-6-(2-methyl-4-(4-(tetrahydro-2H-pyran-2-yl)-4H-1,2,4-triazol-3-yl)phenyl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-onein ethanol at 80° C. The resulting mixture was stirred vigorously andheated at 80° C. under a reflux condenser under nitrogen for 70 min. Theresulting mixture was filtered and purified using reverse-phasepreparatory HPLC (10-65% acetonitrile+0.1% TFA in water+0.1% TFA, over30 min). Fractions containing the desired product were combined,neutralized with saturated aqueous sodium bicarbonate and theacetonitrile removed under reduced pressure. Solids were collected byvacuum filtration, washed thoroughly with water and diethyl ether anddried under high vacuum at 50° C. to give the desired product in 48%yield. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 11.32 (br. s., 1H), 8.44 (br.s., 1H), 7.96 (s, 1H), 7.90 (d, J=8.59 Hz, 1H), 7.70 (s, 1H), 7.56 (d,J=7.81 Hz, 1H), 3.78 (dd, J=2.93, 11.13 Hz, 2H), 3.52-3.64 (m, 2H), 3.23(t, J=10.93 Hz, 2H), 2.48 (s, 3H), 1.51-1.66 (m, 5H), 1.49 (s, 6H),1.11-1.26 (m, 2H); MS (ESI) m/z 448.3 [M+1]⁺.

Example 37-(2-Methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-onehydrochloride

A. Ethyl2-(5-bromo-3-(2,4-dimethoxybenzylamino)pyrazin-2-ylamino)acetate

Ethyl 2-(3,5-dibromopyrazin-2-ylamino)acetate (See Example 1.C) (1.06 g,3.13 mmol), (2,4-dimethoxyphenyl)methanamine (0.601 g, 3.60 mmol),N,N-diisopropylethylamine (1.63 mL, 9.38 mmol) and dimethylsulfoxide(1.6 mL) were combined in a microwave vial with a stirbar and heated ina microwave reactor at 150° C. for 2 h. The resulting mixture waspurified using flash chromatography (5-60% ethyl acetate in hexane).Fractions containing the desired product were combined and concentratednearly to dryness under reduced pressure. Ethyl acetate (2 mL) andhexane (18 mL) was added. The resulting solids were collected by vacuumfiltration, washed with hexane and dried under high vacuum to give thedesired product (0.636 g, 1.495 mmol, 48% yield) as a light pink solid.¹H NMR (300 MHz, DMSO-d₆) δ (ppm) 7.24 (s, 1H), 7.19 (d, J=8.52 Hz, 1H),7.11 (t, J=5.63 Hz, 1H), 6.84 (t, J=4.81 Hz, 1H), 6.59 (d, J=2.47 Hz,1H), 6.50 (dd, J=2.20, 8.24 Hz, 1H), 4.37 (d, J=4.67 Hz, 2H), 3.96-4.15(m, 4H), 3.81 (s, 3H), 3.75 (s, 3H), 1.17 (t, 3H); MS (ESI) m/z 425.3[M]⁺, 426.9 [M+2]⁺.

B. 7-Bromo-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one trifluoroacetate

Ethyl 2-(5-bromo-3-(2,4-dimethoxybenzylamino)pyrazin-2-ylamino)acetate(0.484 g, 1.138 mmol), methanol (0.461 mL, 11.38 mmol) and TFA (7 mL)were combined in a sealable vessel with a stirbar. The system was purgedwith nitrogen. The resulting mixture was sealed, stirred vigorously andheated at 75° C. in an oil bath for 25 min. The resulting mixture wasdiluted with water (14 mL) and stirred at room temperature for 5 min.Solids were collected by vacuum filtration, washed with water anddiethyl ether and dried under high vacuum to give the desired product(0.375 g, 1.093 mmol, 96% yield) as a pink solid. MS (ESI) m/z 229.0[M]⁺, 231.3 [M+2]⁺.

C.7-(2-Methyl-4-(4-(tetrahydro-2H-pyran-2-yl)-4H-1,2,4-triazol-3-yl)phenyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

3-(3-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(tetrahydro-2H-pyran-2-yl)-4H-1,2,4-triazole(See Example 2.C) (0.465 g, 1.259 mmol),7-bromo-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one trifluoroacetate(0.432 g, 1.259 mmol),[1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (0.103 g, 0.126 mmol), sodium carbonate (1 Min water, 3.78 mL, 3.78 mmol), 1,4-dioxane (2.5 mL) and isopropanol (1mL) were combined in a sealable vessel with a stirbar. The system waspurged with nitrogen. The resulting mixture was sealed, stirredvigorously and heated at 100° C. for 70 min. The resulting mixture wasdiluted with water and dichloromethane and filtered through a frittedfunnel. Solids were washed with 20% methanol in dichloromethane.Filtrate and wash were combined and the solvent was removed underreduced pressure. The residue was triturated with acetonitrile. Waterwas added. Solids were collected by vacuum filtration and washedthoroughly with water and diethyl ether. Solids were washed with 20%methanol in dichloromethane. Filtrate and wash were combined and thesolvent was removed under reduced pressure. The residue was taken up inhot DMSO and methanol, filtered and purified using reverse-phasepreparatory HPLC (20-65% acetonitrile+0.1% TFA in water+0.1% TFA, over30 min). Fractions containing the desired product were combined,neutralized with saturated aqueous sodium bicarbonate and concentratednearly to dryness under reduced pressure. Solids were collected byvacuum filtration, washed with water and dried under high vacuum to givethe desired product (0.072 g, 0.184 mmol, 15% yield) as an off-whitesolid. MS (ESI) m/z 392.1 [M+1]⁺.

D.7-(2-Methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-onehydrochloride

Hydrochloric acid (6 N in water 0.149 mL, 0.894 mmol) was added to astirred mixture of7-(2-methyl-4-(4-(tetrahydro-2H-pyran-2-yl)-4H-1,2,4-triazol-3-yl)phenyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one(0.070 g, 0.179 mmol) in ethanol (3 mL) at 80° C. The system was purgedwith nitrogen. The resulting mixture was sealed and heated at 80° C. Theresulting mixture was heated at 80° C. for 25 min and then cooled toroom temperature. Solids were collected by filtration, washed withmethanol and dried under high vacuum at 40° C. to give the desiredproduct (0.058 g, 0.169 mmol, 94% yield) as a white solid. ¹H NMR (300MHz, DMSO-d₆) δ (ppm) 11.32 (s, 1H), 8.66 (s, 1H), 7.97 (s, 1H), 7.92(dd, J=1.37, 7.97 Hz, 1H), 7.74 (s, 1H), 7.50 (d, J=7.97 Hz, 1H), 4.14(s, 2H), 2.44 (s, 3H); MS (ESI) m/z 308.3 [M+1]⁺.

Example 46-(4-(2-Hydroxypropan-2-yl)phenyl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

A. 2-Bromo-N-(3,5-dibromopyrazin-2-yl)acetamide

A solution of 2-amino-3,5-dibromopyrazine (6.17 g, 23.7 mmol) andbromoacetic anhydride (3.0 g, 11.9 mmol) in acetonitrile (40 mL) wasstirred at 70° C. Upon complete consumption of starting material (byTLC), the solution was condensed and partitioned between water and ethylacetate (3×). The organic layers were combined, dried over magnesiumsulfate, filtered and the solvent was removed under reduced pressure.The resulting material was purified using Biotage column chromatography(5-80% ethyl acetate in hexanes) to afford the title compound (3.78 g,10.1 mmol, 85% yield). MS (ESI) m/z 372.1 [M−2]⁺, 374.0 [M]⁺, 376.1[M+2]⁺, 378.3 [M+4]⁺.

B.6-Bromo-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

2-Bromo-N-(3,5-dibromopyrazin-2-yl)acetamide (3.30 g, 8.83 mmol) and2-(tetrahydro-2H-pyran-4-yl)ethanamine hydrochloride (1.46, 8.83 mmol)and diisopropyl ethylamine (6.67 mL, 35.3 mmol) were combined and heatedat 85° C. Upon complete consumption of starting material (by TLC), thereaction solution was condensed and purified via Biotage chromatography(0-100% ethyl acetate in hexanes) to afford the title compound (1.53 g,4.48 mmol, 50% yield). MS (ESI) m/z 341.4 [M]⁺, 343.1 [M+2]⁺.

C. 2-(4-Bromophenyl)propan-2-ol

1-(4-Bromophenyl)ethanone (9.25 g, 46.5 mmol) was dissolved intetrahydrofuran (200 mL). The solution was cooled in a −50° C. bath.Methylmagnesium bromide (3M in ether, 46.5 mL, 139 mmol) was added overa 15 min period. The reaction was allowed to warm to room temperatureand then stirred for 20 h. The reaction was quenched with saturatedammonium chloride and then extracted with ethyl acetate. The organiclayer was dried over magnesium sulfate, filtered and concentrated togive an oil. The oil was purified on a silica gel column (0-20% ethylacetate in hexanes) to give the product a colorless oil (9.1 g, 46.2mmol, 91% yield). MS (ESI) m/z 197.1 [M]⁺, 199.1 [M+2]⁺.

D. 2-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol

2-(4-Bromophenyl)propan-2-ol (4.7 g, 21.85 mmol), bis(pinacolato)diboron(6.66 g, 26.2 mmol), potassium acetate (6.43 g, 65.6 mmol) and dimethylsulfoxide (50 mL) were stirred and degassed under vacuum for 10 min.[1,1′-Bis(diphenyl-phosphino)ferrocene]dichloro-palladium(II) complexwith dichloromethane (1:1) (0.892 g, 1.093 mmol) was added and thereaction was degassed for another 5 min. The reaction was then heated to80° C. under nitrogen for 2 h. The reaction was cooled to roomtemperature and then extracted with 1:1 ether:ethyl acetate and water.The resulting black emulsion was filtered through a pad of celite andthe filtrate combined with extraction layers. The organic layer wasdried over magnesium sulfate, filtered and then purified on silica gelcolumn (0-25% ethyl acetate in hexanes). The product fractions wereconcentrated and then triturated in hexanes to give a white solid, (4.0g, 15.3 mmol, 70% yield). MS (ESI) m/z 263.3 [M+1]⁺.

E.6-(4-(2-Hydroxypropan-2-yl)phenyl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

6-Bromo-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one(0.250 g, 0.733 mmol),2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol(0.192 g, 0.733 mmol) anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane (0.030 g, 0.037 mmol) were combined in dimethylformamide(1.0 mL). Sodium carbonate (0.311 g, 2.93 mmol) in water (0.2 mL) wasadded and the reaction solution was then heated in a Biotage EmrysOptimizer microwave reactor at 120° C. for 15 min. The cooled reactionsolution was filtered through Celite and the filter cake was washed withethyl acetate. Filtrate and ethyl acetate wash were combined and solventremoved under reduced pressure. The resulting material was purifiedusing Biotage column chromatography (0-5% methanol in ethyl acetate)followed by trituration with dimethylformamide and water to afford thetitle compound (0.074 g, 0.19 mmol, 25%) ¹H NMR (400 MHz, DMSO-d₆) δ(ppm) 12.24 (s, 1H), 7.98 (s, 1H), 7.89 (d, J=8.39 Hz, 2H), 7.53 (d,J=8.39 Hz, 1H), 5.04 (s, 1H), 4.16 (s, 1H), 3.82 (dd, J=11.1, 2.39 Hz,2H), 3.61 (t, J=7.59 Hz, 2H), 3.25 (t, J=9.59 Hz, 3H), 1.70 (s, 1H),1.66 (s, 1H), 1.58 (m, 3H), 1.44 (s, 6H), 1.25 (m, 2H); MS (ESI) m/z397.2 [M+1]⁺; mp 210-212° C.

Example 56-(6-(2-Hydroxypropan-2-yl)pyridin-3-yl)-4-(2-morpholinoethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

A. 2-Chloro-N-(3,5-dibromopyrazin-2-yl)acetamide

A solution of 2-amino-3,5-dibromopyrazine (3.0 g, 11.9 mmol) andchloroacetic anhydride (4.2 g, 8.7 mmol) were reacted in acetonitrile(10 mL) at 70° C. for 16 h. The solution was condensed and diluted withethyl acetate. The organics were washed with a 1:1 solution of sodiumbicarbonate (saturated) and potassium carbonate (1.75 M in water) (4×).The organics were combined, dried over magnesium sulfate, filtered andsolvent removed under reduced pressure. The resulting solid wastriturated with 10% ethyl acetate in hexanes to afford the titlecompound (3.12 g, 9.3 mmol, 72% yield). MS (ESI) m/z 328.3 [M−1]⁺, 330.4[M+1]⁺, 332.3 [M+3]⁺.

B. N-(3,5-Dibromopyrazin-2-yl)-2-iodoacetamide

To a solution of 2-chloro-N-(3,5-dibromopyrazin-2-yl)acetamide (3.0 g,9.11 mmol) in acetone (40 mL) was added sodium iodide (13.65 g, 91 mmol)dissolved in acetone (20 mL). Solution was allowed to stir at ambienttemperature for 16 h. Solution was condensed under reduced pressure anddiluted with ethyl acetate (500 mL) and washed consecutively with water(5×) to remove the blue color. Organics were dried over magnesiumsulfate, filtered and solvent removed under reduced pressure to affordthe crude product. The solid was diluted with 10% ethyl acetate inhexanes (40 mL) and sonicated while scraping the sides of the flask. Thesolution was then heated under a heat gun for 5 min, then cooled whilesonicating at ambient temperature. The resulting solid was filtered andwashed with additional hexanes and dried under vacuum to afford thetitle compound (3.0 g, 7.13 mmol, 78% yield). MS (ESI) m/z 420.3 [M−1]⁺,422.0 [M+1]⁺, 424.0 [M+3]⁺.

C.6-Bromo-4-(2-morpholinoethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

N-(3,5-Dibromopyrazin-2-yl)-2-iodoacetamide (0.5 g, 1.188 mmol),diisopropylethylamine (0.415 mL, 2.376 mmol) and 2-morpholinoethanamine(0.162 g, 1.248 mmol) were combined in acetonitrile (5 mL). The solutionwas heated to 45° C. for 1 h. Solution was condensed and diluted with75% ethyl acetate in hexanes. The resulting solid was filtered and thefiltrate collected and condensed followed by purification via Biotagechromatography (0-75% ethyl acetate in hexanes then 0-10% methanol inethyl acetate) to afford the title compound (0.228 g, 0.67 mmol, 56%yield). MS (ESI) m/z 342.4 [M]⁺, 344.4 [M+2]⁺.

D. 2-(5-Bromopyridin-2-yl)propan-2-ol

2,5-Dibromopyridine (1.04 g, 4.39 mmol) was dissolved in toluene (22 mL)in a 100 mL round-bottomed flask. The mixture was cooled to −78° C.n-Butyllithium (3.02 mL, 4.83 mmol) was added dropwise. The mixture wasstirred 30 min, followed by the addition of acetone (2 mL). The mixturewas stirred 40 min and then let warm to rt. The mixture was washed withammonium chloride (5% aq, 50 mL), water (50 mL) and then brine (50 mL).The organic layer was dried over sodium sulfate, filtered andconcentrated. The residue was purified by Biotage (16% ethyl acetate inhexanes). Concentration of the desired fractions afforded the product(0.82 g, 3.78 mmol, 86% yield). MS (ESI) m/z 216.0 [M]⁺, 218.1 [M+2]⁺.

E. 2-(5-(Trimethylstannyl)pyridin-2-yl)propan-2-ol

2-(5-Bromopyridin-2-yl)propan-2-ol (0.34 g, 1.574 mmol),1,1,1,2,2,2-hexamethyldistannane (0.361 mL, 1.652 mmol) andtetrakis(triphenylphosphine)palladium(0) (0.182 g, 0.157 mmol) werecombined in toluene (5 mL) in a 50 mL resealable flask. The reaction wasstirred at 115° C. for 1.5 h. The mixture was then concentrated to abouta 2 mL volume. The residue was purified via Biotage (16% ethyl acetatein hexanes). Concentration of the desired fractions afforded the titlecompound (0.33 g, 1.10 mmol, 70% yield). MS (ESI) m/z 302.1 [M+1]⁺.

F.6-(6-(2-Hydroxypropan-2-yl)pyridin-3-yl)-4-(2-morpholinoethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

6-Bromo-4-(2-morpholinoethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one(0.228 g, 0.666 mmol) and2-(5-(trimethylstannyl)pyridin-2-yl)propan-2-ol (0.220 g, 0.733 mmol)were combined in dimethylformamide (3 mL). Solution was purged withnitrogen gas followed by the addition ofdichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane (0.109 g, 0.133 mmol). Solution was heated to 100° C.for 2 h. Solution was condensed under reduced pressure and the resultingoil purified via reverse-phase-preparative HPLC (5-60% acetonitrile+0.1%TFA in H₂O+0.1% TFA, over 30 min) and desired fractions were loaded ontoa Strata-XC ion exchange column. The column was washed successively withwater, acetonitrile, methanol and 5% ammonium hydroxide in methanol. Theproduct eluted with the 5% ammonium hydroxide in methanol and wasconcentrated under reduced pressure and dried to afford the titlecompound (0.070 g, 0.18 mmol, 26% yield). ¹H NMR (400 MHz, DMSO-d₆) δ(ppm) 11.33 (br. s., 1H), 9.05 (d, J=1.56 Hz, 1H), 8.27 (dd, J=8.59,2.34 Hz, 1H), 8.06 (s, 1H), 7.72 (d, J=8.59 Hz, 1H), 5.27 (s, 1H), 4.29(s, 2H), 3.71 (t, J=6.44 Hz, 2H), 3.54 (t, J=4.49 Hz, 4H), 2.62 (t,J=6.44 Hz, 2H), 2.40-2.48 (m, 4H), 1.46 (s, 6H); MS (ESI) m/z 399.2[M+1]⁺; mp 239-241° C.

Example 61-(((trans)-4-Methoxycyclohexyl)methyl)-7-(4-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

A. 5-Bromo-4-methylpicolinonitrile

2,5-Dibromo-4-methylpyridine (5.0 g, 19.9 mmol), copper cyanide (1.43 g,15.9 mmol), sodium cyanide (0.801 g, 16.3 mmol) and dimethylformamide(30 mL) were combined in a sealed reaction vessel and heated at 158° C.for 3 h. The reaction mixture was purified by silica gel columnchromatography (0-80% ethyl acetate in hexanes). The resulting materialwas subjected to a second silica gel column (0-20% methanol indichloromethane). Clean fractions were combined and concentrated toafford the title compound as a white solid (2.30 g, 11.6 mmol, 58%yield). MS (ESI) m/z 198.0 [M+1]⁺.

B. Ethyl 2-(3,5-dibromopyrazin-2-ylamino)acetate

A 2000 mL 3-necked round bottomed flask was charged with2-amino-3,5-dibromopyrazine (172 g, 680 mmol) in dimethylformamide (860mL) and cooled to 0-5° C. Cesium carbonate (288 g, 884 mmol) was addedin one portion followed by the portion-wise addition of ethylchloroacetate (87 mL, 816 mmol). The solution was allowed to warm to20-25° C. then heated to 55° C. (exotherm observed, max temperatureobserved 76° C.). Once the internal reaction temperature subsided to 65°C. the reaction was heated at 65° C. for ˜4 h. The reaction was cooledto 20-25° C. and filtered through filter paper to remove inorganic saltsand the solid was washed with dimethylformamide (3 vol). The filtratewas added dropwise to 16 vol of ice-water (8 vol ice/8 vol water) andthe slurry was allowed to agitate for 12-24 h. The resulting brown solidwas isolated following filtration and washed with water (10 vol) andair-dried. Crude product was dissolved in methyl t-butyl ether (3.46 L,15 vol). Charcoal (C-906 from Ecosorb, 20 wt %, 46.1 g) was added andthe mixture was heated at reflux for 1 h. After cooling to rt, thecharcoal was removed over a Celite bed and the filtrate was concentratedto dryness. The crude was dissolved in ethyl acetate (576 mL, 2.5 vol)and concentrated to a thick slurry. A solution of 2% ethyl acetate inheptane (1.15 L, 5 vol) was added and the mixture was stirred at rt for30-60 min. The product was collected by filtration, washed with heptane(2-3 vol) and dried under high vacuum at 35-40° C. for 16 h to affordthe desired compound as an off-white solid (109 g, 47% yield). A secondcrop was isolated from the mother liquor as follows: the filtrate wasconcentrated to give a crude oil. Ethyl acetate (1 vol.) was added. Theresulting solution was seeded with previously isolated product andcooled at 0-5° C. for 1 h. The resulting solid was collected byfiltration and washed with cold ethyl acetate:heptane (1:1 mixture, <1vol). The solid was dried as described previously and combined with thefirst crop to provide the title compound (132 g, 57% total yield). MS(ESI) m/z 337.8 [M−1]⁺, 339.8 [M+1]⁺, 341.8 [M+3]⁺.

C.7-Bromo-1-(((trans)-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

A solution of ethyl 2-(3,5-dibromopyrazin-2-ylamino)acetate (500 mg,1.47 mmol), ((trans)-4-methoxycyclohexyl)methanamine (317 mg, 2.21 mmol)and diisopropylethyl amine (0.77 mL, 4.42 mmol) in anhydrousdimethylsulfoxide (8.0 mL) was placed in a microwave vessel (20 mL). Thereaction was heated to 150° C. for 1 h. The reaction was poured intowater, extracted with ethyl acetate (2×100 mL), dried over sodiumsulfate, filtered and concentrated under reduced pressure. The resultingmaterial was dissolved in acetic acid (30 mL) and placed in a sealedtube. The reaction was heated to 120° C. overnight. The solution wascooled, concentrated under reduced pressure, neutralized with saturatedsodium bicarbonate, extracted with ethyl acetate (3×100 mL), dried oversodium sulfate, filtered and adsorbed onto silica gel. Purification byflash chromatography (50% ethyl acetate in hexanes) gave a light orangesolid (400 mg, 1.12 mmol, 76% yield). MS (ESI) m/z 355.2 [M+]⁺, 357.2{M+2]⁺.

D.1-(((trans)-4-Methoxycyclohexyl)methyl)-7-(trimethylstannyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

7-Bromo-1-(((trans)-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one(2.71 g, 7.63 mmol), 1,1,1,2,2,2-hexamethyldistannane (3.00 g, 9.15mmol) and tetrakis(triphenylphosphine)palladium(0) (882 mg, 0.76 mmol)were combined in a sealed tube charged with anhydrous dioxane (40 mL)and purged with nitrogen gas. The reaction was heated to 100° C. for 4h. The reaction was diluted with ethyl acetate, filtered through celite,washed celite with ethyl acetate and the filtrate concentrated underreduced pressure. The crude material was purified by flashchromatography (0-50% ethyl acetate in hexane) and desired fractionswere combined and concentrated to give a light yellow solid (2.32 g,5.28 mmol, 69% yield). MS (ESI) m/z 441.1 [M+1]⁺.

E.5-(8-(((trans)-4-Methoxycyclohexyl)methyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-4-methylpicolinonitrile

1-(((trans)-4-Methoxycyclohexyl)methyl)-7-(trimethylstannyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one(0.721 g, 1.64 mmol), 5-bromo-4-methylpicolinonitrile (0.323 g, 1.64mmol), tris(dibenzylideneacetone)dipalladium(0) (0.150 g, 0.164 mmol),triethylamine (0.687 mL, 4.93 mmol), tri-ortho-toylphosphine (0.100 g,0.328 mmol) and dimethylformamide (8 mL) were combined in a sealedreaction vessel. Nitrogen was bubbled through the reaction for 5 min andreaction was heated at 100° C. for 3 h. Reaction is filtered,concentrated and purified by silica gel column chromatography (0-80%ethyl acetate in hexanes). Fractions were combined and concentrated toafford the crude title compound used directly for next step (0.607 g,1.55 mmol, 94% yield). MS (ESI) m/z 393.5 [M+1]⁺.

F.5-(8-(((trans)-4-Methoxycyclohexyl)methyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-4-methylpicolinamide

5-(8-(((trans)-4-Methoxycyclohexyl)methyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-4-methylpicolinonitrile(0.607 g, 1.55 mmol), trifluoroacetic acid (2.0 mL, 26.0 mmol) andsulfuric acid (0.5 mL, 9.38 mmol) were combined and heated at 65° C. for1 h. Reaction pH was adjusted to 10 with sodium carbonate and theresulting solution was extracted with ethyl acetate (3×15 mL). Organiclayers were collected, dried over magnesium sulfate, concentrated andpurified using reverse-phase preparatory HPLC (10-100% acetonitrile+0.1%TFA in H₂O+0.1% TFA, over 30 min). Clean fractions were combined andcondensed under reduced pressure and dried under high vacuum to affordthe title compound as a yellow solid (0.425 g, 1.04 mmol, 67% yield). MS(ESI) m/z 411.5 [M+1]⁺.

G.(Z)—N-((Dimethylamino)methylene)-5-(8-(((trans)-4-methoxycyclohexyl)methyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-4-methylpicolinamide

5-(8-(((trans)-4-Methoxycyclohexyl)methyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-4-methylpicolinamide(0.412 g, 1.00 mmol), dimethylformamide dineopentylacetal (1.5 mL) andtetrahydrofuran (10 mL) were combined and heated at 85° C. for 3 h.Reaction was concentrated under a stream of nitrogen placed in reactionvessel. Crude product was used directly for next step (0.467 g, 1.00mmol, 100% yield). MS (ESI) m/z 466.6 [M+1]⁺

H.1-(((trans)-4-Methoxycyclohexyl)methyl)-7-(4-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

(Z)—N-((Dimethylamino)methylene)-5-(8-(((trans)-4-methoxycyclohexyl)methyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-4-methylpicolinamide(0.467 g, 1.00 mmol) was added to acetic acid (6 mL). The reaction wascooled to 0° C. and hydrazine (1.00 mL, 32 mmol) was added dropwise. Thereaction was allowed to stir and warm to 25° C. over 10 min. Reactionwas concentrated under a stream of nitrogen placed in reaction vessel.Water (5 mL) was added and the product was collected by filtration andpurified using reverse-phase semi-preparatory HPLC (20-70%acetonitrile+0.1% TFA in H₂O+0.1% TFA, over 30 min). Clean fractionswere combined and condensed under reduced pressure and dried under highvacuum to afford the title compound as a yellow solid (0.046 g, 0.106mmol, 11% yield). ¹H NMR (400 MHz, METHANOL-d₄) δ (ppm) 8.72 (s, 1H),8.62 (s, 1H), 8.37 (s, 1H), 7.93 (s, 1H), 4.30 (s, 2H), 3.99 (d, J=7.03Hz, 2H), 3.32 (s, 3H), 3.08-3.17 (m, 1H), 2.71-2.76 (m, 3H), 2.06 (br.s., 2H), 1.80-1.89 (m, 1H), 1.74 (br. s., 2H), 1.09 (d, J=11.32 Hz, 4H);MS (ESI) m/z 435.5 [M+1]⁺.

Example 77-(5-Fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-isopropyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

A. Ethyl 2-(5-bromo-3-(isopropylamino)pyrazin-2-ylamino)acetate

A mixture of ethyl 2-(3,5-dibromopyrazin-2-ylamino)acetate (See Example6.B) (1.5 g, 4.43 mmol), isopropylamine (0.17 g, 4.87 mmol),N,N-diisopropylethylamine (1.14 g, 8.84 mmol) and dimethylsulfoxide (10mL) in a reaction vial was heated in an oil bath at 150° C. for 16 h.After being cooled to room temperature, the resulting mixture was pouredinto water and extracted with ethyl acetate. The organic layer was driedover sodium sulfate, filtered, evaporated under reduced pressure andpurified on silica gel column chromatography (10-20% ethyl acetate inpetroleum ether) to give the title compound (780 mg, 55.7% yield). MS(ESI) m/z 316.9 [M+1]⁺.

B. 7-Bromo-1-isopropyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

A mixture of ethyl2-(5-bromo-3-(isopropylamino)pyrazin-2-ylamino)acetate (780 mg, 2.26mmol), methanol (5 mL) and TFA (10 mL) in a sealable vessel was purgedwith nitrogen, sealed, stirred vigorously and heated at 90° C. with anoil bath for 16 h. The resulting mixture was diluted with methanol andthe solvent was removed under reduced pressure. Methanol (10 mL) wasadded and the solvent was removed under reduced pressure again. Methanol(10 mL) and sodium bicarbonate were added. The resulting mixture wasstirred at room temperature until pH=6 (in water), the solvent wasremoved under reduced pressure. Water (20 mL) was added. The mixture wasextracted with methylene chloride (20 mL×3). The organic layer was driedover anhydrous sodium sulfate, concentrated to give the crude productand purified on silica column chromatography (10-20% ethyl acetate inpetroleum ether) to give the title compound (360 mg, 39.4% yield).

C.1-Isopropyl-7-(trimethylstannyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

7-Bromo-1-isopropyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (0.5 g,1.844 mmol), hexamethylditin (0.725 g, 2.213 mmol),tetrakis(triphenylphosphine)palladium(0) (0.213 g, 0.184 mmol) and1,4-dioxane (3 mL) were combined in a sealable vessel with a stirbar.Nitrogen gas was bubbled through the solution. The vessel was sealed,stirred vigorously and heated at 100° C. for 2 h. The resulting cloudyblack mixture was diluted with ethyl acetate, filtered and the filtercake washed thoroughly with ethyl acetate. The filtrate was concentratedunder reduced pressure and purified using silica gel flash columnchromatography (20-80% ethyl acetate in hexanes) to give the desiredproduct (0.49 g, 1.38 mmol, 75% yield) as a yellow-white solid. MS (ESI)m/z 357.4 [M+2]⁺.

D. 4-Bromo-2-fluoro-5-methylbenzamide

To a solution of 4-bromo-2-fluoro-5-methylbenzonitrile (40 g, 190 mmol)in a mixture of sulfuric acid (98%) and TFA (v/v=4:1, 480 mL) wasstirred at 80° C. for 16 h. After the mixture was cooled to roomtemperature, the resulting mixture was poured into ice-cold water. Theresulting precipitate was collected by filtration, washed with water anddried under reduced pressure to give the title compound (41 g, 95%yield) as a white solid. MS (ESI) m/z 232.0 [M+1]⁺.

E. 4-Bromo-N-((dimethylamino)methylene)-2-fluoro-5-methylbenzamide

A solution of 4-bromo-2-fluoro-5-methylbenzamide (20 g, 86 mmol) inN,N-dimethyl-formamide dimethylacetal (200 mL) was stirred at 100° C.under nitrogen for 3 h. The resulting mixture was concentrated and driedto give the desired product (24.6 g, 95% yield) as a yellow oil, whichwas used in the next step without further purification. MS (ESI) m/z287.0 [M+1]⁺.

F. 3-(4-Bromo-2-fluoro-5-methylphenyl)-1H-1,2,4-triazole

To a solution of4-bromo-N-((dimethylamino)methylene)-2-fluoro-5-methylbenzamide (24.6 g,86.2 mmol) in acetic acid (200 mL) was added dropwise hydrazine hydrate(25 mL, 0.70 mol) at 0° C. The reaction mixture was stirred at roomtemperature overnight. The mixture was filtered washed with water (500mL×3) and dried under reduced pressure to give the title compound (15 g,68% yield) as a white solid. MS (ESI) m/z 256.0 [M+1]⁺.

G.3-(4-Bromo-2-fluoro-5-methylphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazole

A solution of 3-(4-bromo-2-fluoro-5-methylphenyl)-1H-1,2,4-triazole (15g, 60 mmol), toluene-4-sulfonic acid (2.0 g, 12 mmol) and3,4-dihydro-2H-pyran (20 g, 240 mmol) in tetrahydrofuran (200 mL) wasstirred at 80° C. under nitrogen for 15 h. The resulting mixture wasconcentrated and purified on silica gel column (1-25% ethyl acetate inpetroleum ether) to give the protected triazole product (15 g, 75%yield) as a white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ (ppm) 8.83 (s,1H), 7.96 (d, J=7.6 Hz, 1H), 7.66 (d, J=10.0 Hz, 1H), 5.61 (dd, J₁=2.4Hz, J₂=9.6 Hz, 1H), 3.96 (d, J=1.6 Hz, 1H), 3.69 (m, 1H), 2.36 (s, 3H),2.00 (m, 2H), 1.70 (m, 2H), 1.57 (m, 2H); MS (ESI) m/z 340.0 [M+1]⁺.

H.7-(5-Fluoro-2-methyl-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)phenyl)-1-isopropyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

1-Isopropyl-7-(trimethylstannyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one(300 mg, 0.84 mmol),3-(4-bromo-2-fluoro-5-methylphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazole(428 mg, 1.26 mmol) and bis(triphenylphosphine)palladium(II) dichloride(56 mg, 0.08 mmol) were combined in N,N-dimethylformamide (5 mL). Themixture was degassed and heated at 140° C. under nitrogen for 3 h. Afterbeing cooled to room temperature, the reaction mixture was filtered andthe filtrate was partitioned between ethyl acetate (15 mL) and water (15mL). The organic layer was separated and the aqueous layer was extractedwith ethyl acetate (10 mL×2). The combined organic layer was dried oversodium sulfate, filtered, concentrated under reduced pressure andpurified by preparative TLC (15% methanol in dichloromethane) to givethe title compound (200 mg, yield 52%) as a solid.

I.7-(5-Fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-isopropyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

A solution of7-(5-fluoro-2-methyl-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)phenyl)-1-isopropyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one(200 mg, 0.44 mmol) in methanolic hydrochloride solution (20 mL, 2 M)was stirred for 5 h at room temperature. The reaction was diluted withsaturated aqueous sodium bicarbonate solution (25 mL) and the aqueousmixture was extracted with ethyl acetate (25 mL×2). The organic phasewas dried over sodium sulfate, filtered, evaporated under reducedpressure and purified on silica gel column (50-100% ethyl acetate inpetroleum ether). The desired fractions were combined and concentratedunder reduced pressure to give the title compound (75 mg, 46% yield). ¹HNMR (DMSO-d₆, 400 MHz): δ (ppm) 14.25 (br. s., 1H), 8.20 (br. s., 1H),7.90 (m, 2H), 7.58 (s, 1H), 7.35 (s, 1H), 5.24 (m, 1H), 4.10 (s, 2H),2.43 (s, 3H), 1.44 (d, J=7.2, 6H); MS (ESI) m/z 368.2 [M+1]⁺.

Example 87′-(2-Methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-1′H-spiro[cyclopropane-1,2′-pyrazino[2,3-b]pyrazin]-3′(4′H)-one

A. tert-Butyl 1-(3,5-dibromopyrazin-2-ylcarbamoyl)cyclopropyl-carbamate

1,1′-Carbonyldiimidazole (4.37 g, 27.0 mmol) was added to a stirredsolution of 1-(tert-butoxycarbonylamino)cyclopropanecarboxylic acid(4.93 g, 24.50 mmol) in N,N-dimethylformamide (6 mL) and dichloromethane(12 mL) at room temperature. The resulting clear yellow mixture wasstirred at room temperature under nitrogen for 4 h.N,N-Diisopropylethylamine (8.54 mL, 49.0 mmol) was added followed by3,5-dibromopyrazin-2-amine (9.29 g, 36.8 mmol). The resulting mixturewas heated at 50° C. under a reflux condenser under nitrogen for 60 h.The resulting mixture was diluted with ethyl acetate and washed withwater. The layers were separated and the organic layer washed withbrine, dried over magnesium sulfate, filtered and concentrated underreduced pressure. The residue was taken up in dichloromethane andpurified using flash chromatography (Biotage) (5-60% ethyl acetate inhexane). Fractions containing the desired product were combined andconcentrated under reduced pressure. The residue was triturated with 15%ethyl acetate in hexane and dried under high vacuum to give the desiredproduct (5.349 g, 12.27 mmol, 50% yield) as an off-white solid. ¹H NMR(400 MHz, DMSO-d₆) δ (ppm) 9.92 (br. s., 1H), 8.76 (s, 1H), 7.70 (br.s., 1H), 1.41 (s, 9H), 1.34-1.40 (m, 2H), 1.02-1.09 (m, 2H); MS (ESI)m/z 437.3 [M+1]⁺, 459.1 [M+Na]⁺.

B. 1-Amino-N-(3,5-dibromopyrazin-2-yl)cyclopropanecarboxamidebistrifluoroacetate

TFA (6.02 mL, 78 mmol) was added to a stirred mixture of tert-butyl1-(3,5-dibromopyrazin-2-ylcarbamoyl)cyclopropylcarbamate (3.410 g, 7.82mmol) in dichloromethane (20 mL). The resulting clear yellow solutionwas stirred at room temperature for 4 h. All volatiles were removedunder reduced pressure and the residue dried under high vacuum at 40° C.to give the desired product (4.42 g, 7.85 mmol, 100% yield) as a waxyyellow solid. MS (ESI) m/z 337.1 [M+1]⁺.

C.7′-Bromo-1′H-spiro[cyclopropane-1,2′-pyrazino[2,3-b]pyrazin]-3′(4′H)-one

1-Amino-N-(3,5-dibromopyrazin-2-yl)cyclopropanecarboxamidebistrifluoroacetate (0.394 g, 0.700 mmol), N,N-diisopropylethylamine(0.610 mL, 3.50 mmol) and 1,4-dioxane (6 mL) were combined in a sealablevessel with a stirbar. The system was purged with nitrogen. Theresulting mixture was sealed, stirred vigorously and heated at 110° C.for 2 h. Volatiles were removed under reduced pressure. The residue wasdissolved in DMSO and methanol, filtered and purified usingreverse-phase preparatory HPLC (10-65% acetonitrile+0.1% TFA inwater+0.1% TFA, over 30 min). Fractions containing the desired productwere combined, neutralized with saturated aqueous sodium bicarbonate andmost of the solvent removed under reduced pressure. Solids werecollected by vacuum filtration, washed thoroughly with water and driedunder high vacuum to give the desired product (0.141 g, 0.553 mmol, 79%yield) as a light yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 11.27(s, 1H), 8.04 (s, 1H), 7.46 (s, 1H), 1.29-1.38 (m, 2H), 0.91-1.01 (m,2H); MS (ESI) m/z 255.1 [M]⁺, 257.0 [M+2]⁺.

D.7′-(2-Methyl-4-(4-(tetrahydro-2H-pyran-2-yl)-4H-1,2,4-triazol-3-yl)phenyl)-1′H-spiro[cyclopropane-1,2′-pyrazino[2,3-b]pyrazin]-3′(4′H)-onetrifluoroacetate

3-(3-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(tetrahydro-2H-pyran-2-yl)-4H-1,2,4-triazole(See Example 2.C) (0.201 g, 0.545 mmol),7′-bromo-1′H-spiro[cyclopropane-1,2′-pyrazino[2,3-b]pyrazin]-3′(4′H)-one(0.139 g, 0.545 mmol),[1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (0.045 g, 0.054 mmol), sodium carbonate (1 Min water, 1.635 mL, 1.635 mmol), 1,4-dioxane (1.2 mL) and isopropanol(0.4 mL) were combined in a sealable vessel with a stirbar. The systemwas purged with nitrogen. The resulting mixture was sealed, stirredvigorously and heated at 100° C. for 1 h. The resulting mixture wasdiluted with water and extracted three times with dichloromethane. Thecombined organics were concentrated under reduced pressure. The residuewas taken up in DMSO and methanol, filtered and purified usingreverse-phase preparatory HPLC (20-70% acetonitrile+0.1% TFA inwater+0.1% TFA, over 30 min). Fractions containing the desired productwere combined and the solvent removed under reduced pressure. Theresidue was dried under high vacuum to give the desired product (0.109g, 0.205 mmol, 38% yield) as an orange solid. MS (ESI) m/z 418.4 [M+1]⁺.

E.7′-(2-Methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-1′H-spiro[cyclopropane-1,2′-pyrazino[2,3-b]pyrazin]-3′(4′H)-one

6 N Hydrochloric acid in water (0.171 mL, 1.025 mmol) was added to astirred mixture of7′-(2-methyl-4-(4-(tetrahydro-2H-pyran-2-yl)-4H-1,2,4-triazol-3-yl)phenyl)-1′H-spiro[cyclopropane-1,2′-pyrazino[2,3-b]pyrazin]-3′(4′H)-onetrifluoroacetate (0.109 g, 0.205 mmol) in ethanol (4 mL) at 80° C. Theresulting mixture was stirred vigorously and heated at 80° C. under areflux condenser under nitrogen for 30 min. The resulting mixture wasfiltered and purified using reverse-phase preparatory HPLC (10-60%acetonitrile+0.1% TFA in water+0.1% TFA, over 30 min). Fractionscontaining the desired product were combined, neutralized with saturatedaqueous sodium bicarbonate and most of the solvent removed under reducedpressure. Solids were collected by vacuum filtration, washed thoroughlywith water and dried under high vacuum at 45° C. to give the desiredproduct (0.027 g, 0.079 mmol, 39% yield) as a yellow solid. ¹H NMR (400MHz, DMSO-d₆) δ (ppm) 11.22 (br. s., 1H), 8.63 (br. s., 1H), 7.93 (s,1H), 7.89 (d, J=7.81 Hz, 1H), 7.62 (s, 1H), 7.58 (s, 1H), 7.47 (br. s.,1H), 2.43 (s, 3H), 1.29-1.38 (m, 2H), 0.95-1.04 (m, 2H); MS (ESI) m/z334.2 [M+1]⁺.

Example 97-(6-(2-Hydroxypropan-2-yl)pyridin-3-yl)-1-((trans)-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

A. Ethyl2-(5-bromo-3-(trans-4-methoxycyclohexylamino)pyrazin-2-ylamino)acetate

Ethyl 2-(3,5-dibromopyrazin-2-ylamino)acetate (See Example 6.B) (30.0 g,88 mmol), trans-4-methoxycyclohexanamine (17.15 g, 133 mmol),N,N-diisopropylethylamine (30.8 mL, 177 mmol) and dimethylsulfoxide(70.8 mL) were combined in a reaction vial with a stirbar and heated inan oil bath at 150° C. for 16 h with stirring. The resulting mixture wasdiluted with ethyl acetate and the volatiles removed under reducedpressure. The residue was purified using silica gel chromatography on aBiotage SP1 (12% ethyl acetate in hexanes). Fractions containing thedesired product were combined and organic volatiles removed underreduced pressure. The residue was triturated with 5% ethyl acetate inhexane. Solids were collected by vacuum filtration, washed with hexaneand dried under vacuum to afford ethyl the title compound (15.37 g, 39.7mmol, 44.8% yield) as an off-white solid. MS (ESI) m/z 387.0 [M]⁺, 389.0[M+2]⁺.

B.7-Bromo-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

The following reaction was split into 3 separate sealed tubes and workedup separately. The material was then combined following purification.Ethyl2-(5-bromo-3-(trans-4-methoxycyclohexylamino)pyrazin-2-ylamino)acetate(10 g, 25.7 mmol), methanol (10.5 mL, 259 mmol) and TFA (100 mL) werecombined in a sealable vessel with a stirbar. The system was purged withnitrogen and the resulting mixture was sealed, stirred vigorously andheated at 90° C. with an oil bath for 18.5 h. The resulting mixture wasdiluted with methanol and all the solvent was removed under reducedpressure. Methanol (100 mL) was added and all the solvent was removedunder reduced pressure again. Methanol (100 mL) and sodium bicarbonate(12.4 g, 147 mmol) were added. The resulting mixture was stirred at roomtemperature until pH=6 (in water). The mixture was concentrated nearlyto dryness. Water (100 mL) was added. The resulting brown solids werecollected by vacuum filtration and washed with water. The brown solidswere dissolved in hot methanol and acetonitrile and purified usingreverse-phase C18 flash column chromatography (20-100% acetonitrile inwater). Fractions containing the desired product were combined andconcentrated nearly to dryness under reduced pressure. Solids werecollected by vacuum filtration, washed with water and dried under highvacuum to give the desired product (4.88 g, 14.3 mmol, 55% yield) as alight tan solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 7.71 (s, 1H), 7.59(s, 1H), 4.66 (tt, J=3.61, 12.20 Hz, 1H), 4.07 (d, J=1.56 Hz, 2H), 3.25(s, 3H), 3.06-3.17 (m, 1H), 2.42 (qd, J=3.51, 12.89 Hz, 2H), 2.10 (d,J=10.93 Hz, 2H), 1.61 (d, J=10.93 Hz, 2H), 1.10-1.24 (m, 2H); MS (ESI)m/z 341.3 [M]⁺, 343.1 [M+2]⁺.

C.7-(6-(2-Hydroxypropan-2-yl)pyridin-3-yl)-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

2-(5-(Trimethylstannyl)pyridin-2-yl)propan-2-ol (See Example 5.E) (9.43g, 31.4 mmol),7-bromo-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one(10.02 g, 29.4 mmol),[1,1′-bis(diphenyl-phosphino)-ferrocene]dichloropalladium(II)dichloromethane adduct (2.398 g, 2.94 mmol) and N,N-dimethylformamide(25 mL) were combined in a round-bottom flask with a stirbar. Theatmosphere in the vessel was removed under vacuum and replaced withnitrogen gas three times. The resulting mixture was stirred vigorouslyand heated at 120° C. under nitrogen for 35 min. The resulting mixturewas purified using flash chromatography, split into 4 separate columns,(2-15% methanol in dichloromethane). Fractions containing the desiredproduct were combined and most of the solvent removed under reducedpressure. The resulting mixture was purified using reverse-phasepreparatory HPLC (20-40% acetonitrile+0.1% TFA in water+0.1% TFA, over30 min), split into 6 runs. Fractions containing the desired productwere combined and all of the acetonitrile and some of the water wereremoved under reduced pressure at 25° C. The remaining yellow solutionwas loaded onto 50 g of Strata X-C ion exchange resin from Phenomenex.The column was washed successively with water, acetonitrile, methanoland then 5% ammonium hydroxide in methanol. The product eluted with the5% ammonium hydroxide in methanol wash and was concentrated underreduced pressure and dried under high vacuum to give the desired product(4.85 g, 12.20 mmol, 42% yield) as a pink foam-solid. ¹H NMR (400 MHz,DMSO-d₆) δ (ppm) 9.03 (d, J=1.56 Hz, 1H), 8.28 (s, 1H), 8.24 (dd,J=2.34, 8.20 Hz, 1H), 7.74 (d, J=7.81 Hz, 1H), 7.61 (s, 1H), 5.26 (s,1H), 4.90 (tt, J=3.71, 12.10 Hz, 1H), 4.13 (s, 2H), 3.28 (s, 3H), 3.20(tt, J=4.00, 10.84 Hz, 1H), 2.58 (qd, J=2.93, 12.82 Hz, 2H), 2.14 (d,J=10.15 Hz, 2H), 1.68 (d, J=10.93 Hz, 2H), 1.47 (s, 6H), 1.17-1.35 (m,2H); MS (ESI) m/z 398.3 [M+1]⁺; mp 196-198° C. (uncorrected).

D.7-(6-(2-Hydroxypropan-2-yl)pyridin-3-yl)-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one(alternate approach)

Ethyl 2-(3,5-dibromopyrazin-2-ylamino)acetate (1 equiv) andtrans-4-methoxycyclohexanamine.hydrochloride (1.5 equiv), NMP and DIEAwere combined and heated to 127° C. and maintained at that temperaturefor 18 h. Upon reaction completion, the mixture was cooled to 35° C.over 4 h. The batch was transferred to a mixture of ethyl acetate and 5%brine. The aqueous layer was removed and the organic layer containingthe batch was washed successively with 5% brine and water. The organiclayer containing the batch was concentrated by vacuum distillation to alow volume, cooled to ambient temperature and the solids were collectedby vacuum filtration. The filter cake was washed with MTBE and theproduct was dried in a vacuum to give 41% yield of ethyl2-(5-bromo-3-(trans-4-methoxycyclohexylamino)pyrazin-2-ylamino)acetate.A mixture of ethyl2-(5-bromo-3-(trans-4-methoxycyclohexylamino)pyrazin-2-ylamino)acetate(1 equiv), water and 85% phosphoric acid (3:1) was heated to 80° C. over1 h. Heating was maintained for 18 h to effect reaction completion. Uponreaction completion, the mixture was cooled to 25° C. and filtered togive a crude product as tan solid. The resulting solids were washed withwater, slurried in water and filtered. The filter cake was washed withwater until the pH of the filtrate was between 4 and 8. The resultingmaterial was dried under vacuum to give 89% yield of7-bromo-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one.7-Bromo-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one(1 equiv),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2-(trimethylsilyloxy)propan-2-yl)pyridine(1 equiv), sodium carbonate (3 equiv) and PdCl₂(AmPhos)₂ (0.003 equiv)were combined in isopropanol and heated at 70° C. for 1.5 h. Standardwork-up and purification afforded the protected compound in 93% yield.Deprotection using standard conditions for removal of atrimethylsilyl-group and isolation gave the title compound.

Example 109-(6-(4H-1,2,4-Triazol-3-yl)-2-methyl-3-pyridyl)-6,11,4a-trihydromorpholino[4,3-e]pyrazino[2,3-b]pyrazin-5-one

A. 5-Bromo-6-methylpicolinonitrile

3,6-Dibromo-2-methylpyridine (4.9 g, 19.53 mmol), copper(I)cyanide (1.75g, 19.53 mmol) and N,N-dimethylformamide (20 mL) were combined in asealable vessel with a stirbar. The resulting mixture was sealed,stirred vigorously and heated at 110° C. for 4 h. The resulting mixturewas diluted with ethyl acetate, poured into a separatory funnelcontaining water and the layers were separated. The water layer wasextracted with ethyl acetate twice. The combined organics were washedwith brine, dried over magnesium sulfate, filtered and concentratedunder reduced pressure. The resulting solid was purified by silica gelchromatography (10% ethyl acetate in hexanes) to give the title compoundas a white solid (1.88 g, 9.54 mmol, 49% yield). MS (ESI) m/z 197.3[M]⁺.

B. tert-Butyl3-(3,5-dibromopyrazin-2-ylcarbamoyl)morpholine-4-carboxylate

A solution of 4-(tert-butoxycarbonyl)morpholine-3-carboxylic acid (1.500g, 6.49 mmol) and 1,1′-carbonyldiimidazole (1.578 g, 9.73 mmol) inN,N-dimethylformamide (2 mL) and dichloromethane (6 mL) was stirred 4.5h at room temperature under nitrogen. N,N-Diisopropylethylamine (2.260mL, 12.97 mmol) was added followed by 3,5-dibromopyrazin-2-amine (3.28g, 12.97 mmol). The resulting mixture was stirred and heated at 50° C.under a reflux condenser under nitrogen for 2 d. The resulting mixturewas concentrated under reduced pressure. The residue was diluted withwater and extracted 3 times with ethyl acetate. The combined organicswere washed with water and brine, dried over magnesium sulfate, filteredand concentrated under reduced pressure. The residue was purified usingflash chromatography (20-30-50% ethyl acetate in hexanes) to give thedesired product (2.136 g, 4.58 mmol, 71% yield) as a slightly yellowfoam-solid. MS (ESI) m/z 467 [M+1]⁺.

C. 9-Bromo-6,11,4a-trihydromorpholino[4,3-e]pyrazino[2,3-b]pyrazin-5-one

tert-Butyl 3-(3,5-dibromopyrazin-2-ylcarbamoyl)morpholine-4-carboxylate(2.132 g, 4.57 mmol) was dissolved in dichloromethane (45 mL) withstirring at room temperature. TFA (9 mL) was added and the resultinglight yellow mixture was capped and stirred at room temperature for 2.5h. The solvent was removed under reduced pressure and the residue driedunder high vacuum at 45° C. to give a viscous yellow oil. The yellow oilwas dissolved in isopropanol (wet) (50 mL) with stirring at roomtemperature. Sodium bicarbonate (3.84 g, 45.7 mmol), palladium(II)acetate (0.103 g, 0.457 mmol) and4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.239 mL, 1.372 mmol)were added. The atmosphere in the flask was removed and replaced withnitrogen. The resulting mixture was stirred vigorously and heated at 80°C. under a reflux condenser under nitrogen for 2 h. The resultingmixture was cooled to room temperature and diluted with water (30 mL).The resulting solids were collected by vacuum filtration, washedthoroughly with water and diethyl ether and dried under high vacuum togive the desired product at ˜90% purity (1.441 g, 5.05 mmol, 99% yield)as a yellow solid. MS (ESI) m/z 285 [M]⁺, 287 [M+2]⁺.

D.9-(1,1-Dimethyl-1-stannaethyl)-6,11,4a-trihydromorpholino[4,3-e]pyrazino[2,3-b]pyrazin-5-one

9-Bromo-6,11,4a-trihydromorpholino[4,3-e]pyrazino[2,3-b]pyrazin-5-one(0.30 g, 1.052 mmol), hexamethylditin (0.414 g, 1.263 mmol),tetrakis(triphenylphosphine)palladium (0) (0.122 g, 0.105 mmol) and1,4-dioxane (5 mL) were combined in a sealable vessel with a stirbar.Nitrogen gas was bubbled through the solution for five min. The vesselwas sealed, stirred vigorously and heated at 100° C. for 2 h. Theresulting cloudy black mixture was diluted with ethyl acetate, filteredand the filter cake washed thoroughly with ethyl acetate. The filtratewas concentrated under reduced pressure and purified using Biotage flashchromatography (20-80% ethyl acetate in hexanes) to give the desiredproduct (0.350 g, 0.948 mmol, 90% yield) as a yellow-white solid. MS(ESI) m/z 369.5 [M]⁺.

E.6-Methyl-5-(5-oxo(6,11,4a-trihydromorpholino[4,3-e]pyrazino[2,3-b]pyrazin-9-yl))pyridine-2-carbonitrile

5-Bromo-6-methylpicolinonitrile (0.080 g, 0.406 mmol),9-(1,1-dimethyl-1-stannaethyl)-6,11,4a-trihydromorpholino[4,3-e]pyrazino[2,3-b]pyrazin-5-one(0.150 g, 0.406 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.041g, 0.045 mmol), tri-o-tolylphosphine (0.027 g, 0.089 mmol) andtriethylamine (0.170 mL, 1.219 mmol) were placed in a sealed tube andN,N-dimethylformamide (2 mL) was added. Nitrogen gas was bubbled throughthe reaction mixture for five minutes and the reaction sealed and heatedat 100° C. for 1 h. The resulting cloudy black mixture was diluted withmethanol, filtered and the filter cake washed thoroughly with methanol.The filtrate was concentrated under reduced pressure and purified usingBiotage flash chromatography (50-100% ethyl acetate in hexanes) to givethe desired product (0.117 g, 0.363 mmol, 89% yield). MS (ESI) m/z 323.5[M+1]⁺

F.6-Methyl-5-(5-oxo(6,11,4a-trihydromorpholino[4,3-e]pyrazino[2,3-b]pyrazin-9-yl))pyridine-2-carboxamide

6-Methyl-5-(5-oxo(6,11,4a-trihydromorpholino[4,3-e]pyrazino[2,3-b]pyrazin-9-yl))pyridine-2-carbonitrile(0.18 g, 0.558 mmol) was placed in a round bottom flask and whilestirring, a mixture of TFA (1.6 mL) and sulfuric acid (0.4 mL) wasadded. The resulting suspension was allowed to stir for 16 h at roomtemperature. The mixture was poured over ice and the excess acid wascarefully neutralized with solid potassium hydroxide. The solid obtainedwas filtered, washed with water and dried under high vacuum to yield thetitle compound (0.153 g, 0.450 mmol, 81% yield) as a red solid. MS (ESI)m/z 341.5 [M+1]⁺

G.9-(6-(4H-1,2,4-Triazol-3-yl)-2-methyl-3-pyridyl)-6,11,4a-trihydromorpholino[4,3-e]pyrazino[2,3-b]pyrazin-5-one

6-Methyl-5-(5-oxo(6,11,4a-trihydromorpholino[4,3-e]pyrazino[2,3-b]pyrazin-9-yl))pyridine-2-carboxamide(0.159 g, 0.467 mmol), N,N-dimethylformamide dineopentyl acetal (2 mL,8.85 mmol) and dimethylsulfoxide (0.5 mL) were placed in a flask andheated to 85° C. for 1 h. The solution was diluted with acetic acid (5mL, 87 mmol) and hydrazine (0.468 mL, 14.90 mmol) was added dropwise.The reaction was allowed to stir at 25° C. for 30 min. The mixture wasconcentrated under reduced pressure and the residue was carefullyneutralized with a saturated aqueous sodium carbonate solution. Thissolution then was extracted with ethyl acetate three times, concentratedunder reduced pressure and purified using reverse-phase semi-preparatoryHPLC (5-50% acetonitrile+0.1% TFA in water+0.1% TFA, over 20 min) toafford the title compound (0.03 g, 0.082 mmol, 17.63% yield). ¹H NMR(400 MHz, DMSO-d₆) δ (ppm) 7.96-8.04 (m, 2H), 7.88 (s, 1H), 4.33 (dd,J=3.71, 10.74 Hz, 1H), 4.15-4.23 (m, 2H), 3.98 (dd, J=3.51, 11.71 Hz,1H), 3.51-3.63 (m, 2H), 2.89-2.99 (m, 1H), 2.70 (s, 3H); MS (ESI) m/z365.5 [M+1]¹

Example 116-(6-(1H-1,2,4-Triazol-3-yl)pyridin-3-yl)-4-(tetrahydro-2h-pyran-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

A.6-Bromo-4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

To a solution of N-(3,5-dibromopyrazin-2-yl)-2-iodoacetamide (SeeExample 5.B) (6.6 g, 15.8 mmol) and diisopropylethylamine (4.0 g, 31.6mmol) in acetonitrile (50 mL) was added tetrahydro-2H-pyran-4-amine (6.4g, 63.2 mmol) and the mixture was stirred at ambient temperature for 16h. The solvent was removed under reduced pressure and the residue whichwas purified by chromatography on silica gel (5-20% ethyl acetate inpetroleum ether) to give the title compound (1.98 g, 40% yield). MS(ESI) m/z 313.1 [M+1]⁺.

B.4-(Tetrahydro-2H-pyran-4-yl)-6-(trimethylstannyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

A degassed mixture of6-bromo-4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one(1.98 g, 6.35 mmol), tetrakis(triphenylphosphine)palladium (1.45 g, 1.27mmol) and hexamethylditin (4.0 g, 12.7 mmol) in dioxane (10 mL) washeated at 90° C. for 3 h under nitrogen. The reaction mixture wasconcentrated under reduced pressure and purified on silica gel column(10-20% ethyl acetate in petroleum ether) to afford the product (1.07 g,42.3% yield). MS (ESI) m/z 399.1[M+1]⁺.

C.6-(6-(1-(Tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

A mixture of4-(tetrahydro-2H-pyran-4-yl)-6-(trimethylstannyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one(1 equiv),5-bromo-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)pyridine(1.2 equiv), tris(dibenzylideneacetone)dipalladium (0.1 equiv),tri-o-tolylphosphine (0.2 equiv), triethylamine (3 equiv) andN,N-dimethylformamide was heated at 95° C. for 3 h under nitrogen.Concentration and chromatography purification give the desired productin 39% yield. MS (ESI) m/z 463.1 [M+1]⁺.

D.6-(6-(1H-1,2,4-Triazol-3-yl)pyridin-3-yl)-4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

A mixture of6-(6-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-onein methanolic hydrochloride solution was stirred at room temperature for0.5 h. The solvent was evaporated under reduced pressure to give thecrude product, which was washed with N,N-dimethylformamide to afford thetitle compound as a hydrochloride salt in 34% yield. ¹H NMR (DMSO-d₆,400 MHz) δ (ppm) 11.44 (s, 1H), 9.30 (s, 1H), 8.59 (d, J=8.4 Hz, 1H),8.46 (s, 1H), 8.22 (m, 2H), 4.70 (t, J=10 Hz, 1H), 4.16 (s, 1H), 3.99(m, 4H), 3.51 (t, J=11.2 Hz, 2H), 1.86 (m, 2H), 1.69 (d, J=12.8 Hz, 2H);MS (ESI) m/z 379.1 [M+1]⁺.

Example 121-Ethyl-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

A. 7-Bromo-1-ethyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

A mixture of ethyl 2-(3,5-dibromopyrazin-2-ylamino)acetate (See Example6.B) (1 equiv), ethylamine hydrochloride (3.1 equiv),N,N-diisopropylethylamine (4 equiv) in N-methyl pyrrolidinone was heatedat 105° C. under nitrogen for 14 h. Standard ethyl acetate/water work upgave the crude product in 77% yield. This material was used withoutfurther purificaction. Crude ethyl2-(5-bromo-3-(ethylamino)pyrazin-2-ylamino)acetate and acetic acid werecombined in methanol. The reaction mixture was refluxed at 60-62° C.under nitrogen for 16 h. The reaction was concentrated under reducedpressure and the resultant residue was diluted with methanol andconcentrated. The resultant residue was dissolved in ethyl acetate,treated with sodium carbonate and stirred for 10 min until pH ˜7. Themixture was filtered and washed with ethyl acetate. The filtrate wasconcentrated and purification by a silica gel plug purification using(0-40% ethyl acetate in hexanes) gave the product as a tan solid.Additionally the filter-cake was suspended in water to remove potassiumcarbonate. The remaining solid product was collected by filtration. Theprocess afforded product in a combined yield of 75%.

B.1-Ethyl-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

A mixture of3-Bromo-2-methyl-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)pyridine(1 equiv), bis(pinacolato)diboron (1.05 equiv), potassium acetate (2equiv), potassium carbonate (3 equiv),[1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (0.1 equiv) in anhydrous dioxane was degassedand heated at 90° C. for 2 h. The mixture was cooled to <40° C. and7-bromo-1-ethyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (1 equiv),water and [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II),complex with dichloromethane (1:1) (0.05 equiv) were added. The mixturewas degassed and heated at 65-70° C. under nitrogen for 1 h. The mixturewas cooled to <40° C., diluted with water and ethyl acetate. Standardethyl acetate/water work up followed by flash column chromatography(0-5% methanol in dichloromethane) gave the title compound in 57% yield.¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 7.99 (s, 2H), 7.93 (s, 1H), 7.72 (s,1H), 4.22 (s, 2H), 4.05 (q, J=6.77 Hz, 2H), 2.71 (s, 3H), 1.18 (t,J=7.03 Hz, 3H); MS (ESI) m/z 337.6 [M+1]⁺.

Example 134-((cis)-4-Methoxycyclohexyl)-6-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

A. 5-Bromo-6-methylpicolinamide

A solution of 5-bromo-6-methylpicolinonitrile (1.8 g, 9.14 mmol) in amixture of TFA and sulfuric acid (30 mL, 4:1, V/V) was stirred at 40° C.for 16 h. The reaction mixture was poured into ice water. The resultingsolid was filtered off and washed with water and dried to give thedesired product as a white solid (1.0 g, 4.65 mmol, 54% yield). MS (ESI)m/z 217.1 [M+2]⁺.

B. 3-Bromo-2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridine

5-Bromo-6-methylpicolinamide (1 g, 4.65 mmol) and N,N-dimethylformamidedimethylacetal (20 mL) were combined in a 100 mL round-bottom flask witha stir bar and heated at 85° C. under a reflux condenser under nitrogenfor 3 h. The resulting mixture was concentrated under reduced pressureand dried under vacuum to give yellow oil, which was used in the nextstep without purification. The residue was diluted with acetic acid (10mL) and hydrazine (2.5 mL, 70.3 mmol) was added drop-wise and allowed tostir at room temperature for 5 h. The reaction mixture was poured intoice water. The resulting solid was filtered, washed with water and driedto give the desired product as a white solid. The aqueous filtrate wasextracted with dichloromethane. The organic layer was concentrated underreduced pressure nearly to dryness to yield additional material.Combination of two batches gave the desired product (0.7 g, 2.9 mmol,63% yield). MS (ESI) m/z 241.1 [M+2]⁺.

C.3-Bromo-2-methyl-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)pyridine

3-Bromo-2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridine (0.7 g, 2.93 mmol)and 3,4-dihydro-2H-pyran (0.493 g, 5.86 mmol) were dissolved intetrahydrofuran (20 mL). TFA (3.34 mg, 0.029 mmol) was added and theresulting solution was heated to 70° C. for 16 h. The reaction mixturewas cooled to room temperature, diluted with ethyl acetate, filtered andpoured into a separatory funnel containing water and ethyl acetate. Theorganic layer was concentrated under reduced pressure. Flashchromatography (0-60% ethyl acetate in hexane) gave the desired productas a white solid (0.40 g, 1.23 mmol, 42% yield). MS (ESI) m/z 325.1[M+2]⁺.

D. (cis)-4-Methoxycyclohexanamine hydrochloride

To a round bottom flask, under nitrogen atmospheretert-butyl(cis)-4-hydroxycyclohexylcarbamate (7.8 g, 36.2 mmol) wasadded and suspended in anhydrous tetrahydrofuran (181.0 mL) and cooledto 0° C. Sodium hydride (2.174 g, 54.3 mmol) was then added and theresulting solution was allowed to stir for 5 min. To a second flaskunder nitrogen atmosphere methyl iodide (2.265 mL, 36.2 mmol) was addedand suspended in anhydrous tetrahydrofuran (10.0 mL). The methyl iodidesolution in tetrahydrofuran was slowly added dropwise to first flaskover 3 min. The reaction was allowed to stir at rt for 16 h. The organicvolatiles were removed under reduced pressure and partitioned betweenethyl acetate (3×) and water. Organic fractions were pooled, dried overmagnesium sulfate, filtered and condensed under reduced pressure. Theresulting material was purified by silica gel column chromatography(25-50% ethyl acetate in hexanes). The desired fractions were combinedand organic volatiles removed under reduced pressure followed by theaddition of hydrochloric acid (4M in 1,4-dioxane, 23.5 mL). Theresulting solution was heated to 40° C. for 1 h and organic volatileswere removed under reduced pressure to afford the title compound (6.0 g,36.2 mmol, 100% yield). MS (ESI) m/z 130.1 [M+1]⁺.

E.6-Bromo-4-((cis)-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

To a solution of N-(3,5-dibromopyrazin-2-yl)-2-iodoacetamide (SeeExample 5.B) (1.0 g, 2.376 mmol) and diisopropylethylamine (1.038 mL,5.94 mmol) in acetonitrile (10 mL) was added(cis)-4-methoxycyclohexanamine hydrochloride (0.413 g, 2.495 mmol). Thesolution was stirred at 55° C. for 3 h. The resulting precipitate wasfiltered and washed with acetonitrile and dried under reduced pressureto afford the title compound (0.442 g, 1.29 mmol, 55% yield). MS (ESI)m/z 341.3 [M]⁺, 343.3 [M+2]⁺.

F.4-((cis)-4-Methoxycyclohexyl)-6-(trimethylstannyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

6-Bromo-4-((cis)-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one(0.442 g, 1.295 mmol), tetrakis(triphenylphosphine)palladium (0.225 g,0.194 mmol) and hexamethylditin (0.322 mL, 1.554 mmol) were combined indioxane (5 mL). The solution was purged with nitrogen gas and heated to90° C. in a screw capped tube for 3 h. The solution was condensed underreduced pressure and purified using Biotage column chromatography (0-50%ethyl acetate in hexanes) to afford the title compound (0.356 g, 0.837mmol, 65% yield). MS (ESI) m/z 426.5 [M+1]⁺, 427.5 [M+1]⁺.

G.4-((cis)-4-Methoxycyclohexyl)-6-(2-methyl-6-(4-(tetrahydro-2H-pyran-2-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

4-((cis)-4-Methoxycyclohexyl)-6-(trimethylstannyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one0.292 g, 0.687 mmol),3-bromo-2-methyl-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)pyridine(0.244 g, 0.756 mmol), tris(dibenzylideneacetone)dipalladium (0.063 g,0.069 mmol), tri-o-tolylphosphine (0.042 g, 0.137 mmol), triethylamine(0.287 mL, 2.061 mmol) and dimethylformamide (5.0 mL) were combined in ascrew capped flask and heated to 95° C. for 1 h. The solution wascondensed under reduced pressure and purified using Biotagechromatography (0-80% ethyl acetate in hexanes followed by 0-10%methanol in ethyl acetate) to afford the title compound (0.279 g, 0.687mmol, 80% yield). MS (ESI) m/z 505.6 [M+1]⁺.

H.4-((cis)-4-Methoxycyclohexyl)-6-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

4-((cis)-4-Methoxycyclohexyl)-6-(2-methyl-6-(4-(tetrahydro-2H-pyran-2-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one(0.279 g, 0.553 mmol) was diluted with ethanol (15 mL) and hydrogenchloride (4.0 N in dioxanes, 5 mL). The solution was stirred at 75° C.for 1 h and at 80° C. for 2 h. The solution was condensed to a slurryand diluted with ethanol and sonicated. The precipitate was filtered andwashed with additional ethanol followed by acetonitrile. The crude solidwas purified using reverse-phased semi-preparative HPLC (10-100%acetonitrile+0.1% TFA in water+0.1% TFA, over 30 min) to afford thetitle compound (0.040 g, 0.095 mmol, 17% yield). ¹H NMR (400 MHz,METHANOL-d₄) δ (ppm) 7.88-8.13 (m, 2H), 7.65 (s, 1H), 4.58 (s, 1H), 4.16(s, 2H), 3.47 (br. s., 1H), 3.22-3.32 (m, 66H), 2.73 (s, 3H), 2.08 (br.s., 2H), 1.91 (br. s., 2H), 1.56 (br. s., 4H); MS (ESI) m/z 421.2[M+1]⁺, mp 192-195° C.

Example 141-Isopropyl-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

A.1-Isopropyl-7-(trimethylstannyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

7-Bromo-1-isopropyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (SeeExample 7.B) (0.5 g, 1.844 mmol), hexamethylditin (0.725 g, 2.213 mmol),tetrakis(triphenylphosphine)palladium(0) (0.213 g, 0.184 mmol) and1,4-dioxane (3 mL) were combined in a sealable vessel with a stirbar.Nitrogen gas was bubbled through the solution. The vessel was sealed,stirred vigorously and heated at 100° C. for 2 h. The resulting cloudyblack mixture was diluted with ethyl acetate, filtered and the filtercake washed thoroughly with ethyl acetate. The filtrate was concentratedunder reduced pressure and purified using silica gel flash columnchromatography (20-80% ethyl acetate in hexanes) to give the desiredproduct (2.410 g, 77% yield) as a yellow-white solid. MS (ESI) m/z 357.4[M+2]⁺

B.1-Isopropyl-7-(2-methyl-6-(4-(tetrahydro-2H-pyran-2-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

To a flask was added3-Bromo-2-methyl-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)pyridine(0.446 g, 1.380 mmol),1-isopropyl-7-(trimethylstannyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one(0.490 g, 1.380 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.139g, 0.152 mmol), tri-o-tolylphosphine (0.092 g, 0.304 mmol),triethylamine (0.577 mL, 4.14 mmol) and N,N-dimethylformamide (3 mL).Nitrogen gas was bubbled through the reaction mixture for 5 min and themixture was heated to 100° C. for 1 h. After cooling to rt, the reactionmixture was filtered through Celite, rinsed with methanol andconcentrated to dryness. The resulting residue was purified by silicagel flash column chromatography (0-80% ethyl acetate in hexanes,followed by 0-10% methanol in dichloromethane) to yield the desiredproduct (0.40 g, 0.921 mmol, 66.7% yield). MS (ESI) m/z 435.5 [M+1]⁺.

C.1-Isopropyl-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

To a stirred mixture of1-isopropyl-7-(2-methyl-6-(4-(tetrahydro-2H-pyran-2-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one(0.400 g, 0.921 mmol) in ethanol (40 mL) at 50° C. was added hydrogenchloride (4 M in dioxane, 1.381 mL, 5.52 mmol). The resulting mixturewas heated at 50° C. under nitrogen for 1 h. The suspension wasconcentrated under reduced pressure and the resulting solid was taken upin dimethylsulfoxide and purified using silica gel chromatography (0-10%ammonia saturated methanol in dichloromethane) to afford the titlecompound (0.200 g, 0.571 mmol, 62.0% yield) as a brown-red solid. ¹H NMR(400 MHz, DMSO-d₆) δ (ppm) 8.10 (br. s., 1H), 8.01 (br. s., 2H), 7.92(s, 1H), 5.26 (quin, J=6.93 Hz, 1H), 4.14 (s, 2H), 3.58 (d, J=5.08 Hz,3H), 1.47 (d, J=6.64 Hz, 6H); MS (ESI) m/z 351.5 [M+1]⁺.

D.1-Isopropyl-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one(alternate approach)

7-Bromo-1-isopropyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (1equiv), bis(pinacolato)diboron) (1 equiv), potassium acetate (3 equiv)and bis(1,1′-bis(diphenylphosphino)ferrocene)palladium (0.01 equiv) werecombined in dioxane, degassed with nitrogen and heated to 95° C. undernitrogen. Dilution with ethyl acetate, filtration through Celite,concentration, trituration with ethyl acetate and hexanes, filtrationand drying gave the boronate ester in 60% yield. tert-Butyl3-(5-bromo-6-methylpyridin-2-yl)-1H-1,2,4-triazole-1-carboxylate (1equiv),1-isopropyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one(1.2 equiv), tetrakis(triphenylphosphine) palladium(0) (0.05 equiv),sodium carbonate (3 equiv) were combined in (3:1) dimethyl acetamide andwater. The mixture was degassed and heated to 100° C. overnight.Standard ethyl acetate/water work up and subsequent trituration in ethylacetate gave the desired product in 41% yield.

Example 157-(1H-Pyrrolo[2,3-b]pyridin-5-yl)-1-(2-(tetrahydro-2h-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

A. Ethyl2-(5-bromo-3-(2-(tetrahydro-2H-pyran-4-yl)ethylamino)pyrazin-2-ylamino)acetate

Ethyl 2-(3,5-dibromopyrazin-2-ylamino)acetate (See Example 6.B) (1.0 g,2.95 mmol) and 2-(tetrahydro-2H-pyran-4-yl)ethanamine (0.381 g, 2.95mmol) were placed in a microwave vial, dimethylsulfoxide (2 mL) wasadded and the resulting mixture was heated in a Biotage Emrys Optimizermicrowave reactor at 150° C. for 3600 s. The crude reaction mixture waspurified using silica gel chromatography (33% ethyl acetate in hexanes)to yield the title compound (0.5 g, 1.3 mmol, 44% yield). MS (ESI) m/z387.1 [M]⁺, 389.1 [M+2]⁺.

B.7-Bromo-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

Ethyl2-(5-bromo-3-(2-(tetrahydro-2H-pyran-4-yl)ethylamino)pyrazin-2-ylamino)acetate(0.5 g, 1.291 mmol) and hydrochloric acid (6 M in water, 0.215 mL, 1.291mmol) were combined in ethanol (2 mL) and the resulting mixture washeated in a Biotage Emrys Optimizer microwave reactor at 100° C. for2400 s. The reaction mixture was concentrated and purified using silicagel chromatography (33% ethyl acetate in hexanes) to yield the titlecompound (quantitative yield). MS (ESI) m/z 341.1 [M]⁺, 343.1 [M+2]⁺.

C.1-(2-(Tetrahydro-2H-pyran-4-yl)ethyl)-7-(trimethylstannyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

7-Bromo-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one(0.4 g, 1.29 mmol), hexamethylditin (0.57 g, 1.75 mmol) andtetrakis(triphenylphosphine)palladium(0) (0.2 g, 0.176 mmol) were placedin a sealed tube with 1,4-dioxane (5 mL). The flask was evacuated,flushed with nitrogen, sealed and heated at 110° C. for 1 h. Thereaction mixture was cooled to room temperature and filtered throughCelite, washing with ethyl acetate. The filtrate was concentrated andsonicated with a small volume of solvent mixture (50% hexane in ethylacetate) and isolated by filtration to yield the title compound (0.34 g,0.8 mmol, 54.6% yield). MS (ESI) m/z 427 [M+2]⁺.

D.7-(1H-Pyrrolo[2,3-b]pyridin-5-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

1-(2-(Tetrahydro-2H-pyran-4-yl)ethyl)-7-(trimethylstannyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one(1.0 g, 2.352 mmol), 5-bromo-1H-pyrrolo[2,3-b]pyridine (0.556 g, 2.82mmol), tris(dibenzylideneacetone)palladium(0) (0.237 g, 0.259 mmol),tri-o-tolylphosphine (0.158 g, 0.518 mmol) and triethylamine (0.984 mL,7.06 mmol) were combined in a sealed tube, dimethylformamide (5 mL) wasadded. The atmosphere in the vessel was removed under vacuum andreplaced with nitrogen gas. The reaction was heated to 100° C. for 1 h.After cooling to room temperature, the reaction mixture was filteredthrough Celite. The filter cake was washed with ethyl acetate. The washand filtrate were combined and concentrated nearly to dryness. Theresulting solid was dissolved in hot methanol, filtered through Celiteand purified by reverse-phase preparative HPLC (5-80% acetonitrile+0.1%TFA in water+0.1% TFA, over 30 min). The clean fractions were collected,neutralized with ammonium hydroxide and concentrated to dryness. Thesolid obtained was filtered, washed with water and dried under highvacuum to yield the title compound (0.10 g, 0.264 mmol, 11.2% yield). ¹HNMR (400 MHz, DMSO-d₆) δ (ppm) 11.71 (br. s., 1H), 8.81 (s, 1H), 8.44(s, 1H), 8.26 (s, 1H), 7.49 (d, J=10.54 Hz, 2H), 6.48 (br. s., 1H), 4.18(s, 2H), 4.13 (t, J=6.44 Hz, 2H), 3.82 (d, J=12.89 Hz, 2H), 3.27 (t,J=11.13 Hz, 2H), 1.71 (d, J=12.49 Hz, 2H), 1.60 (br. s., 3H), 1.24 (d,2H); MS (ESI) m/z 379.2 [M+1]⁺; mp 255-258° C.

Example 166-(6-(2-Hydroxypropan-2-yl)pyridin-3-yl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

A.6-Bromo-4-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

N-(3,5-Dibromopyrazin-2-yl)-2-iodoacetamide (See Example 5.B) (8.0 g,19.01 mmol), (tetrahydro-2H-pyran-4-yl)methanamine (2.63 g, 22.81 mmol)and diisopropylethylamine (6.64 mL, 38.0 mmol) were placed in a 250 mLround bottom flask, suspended in acetonitrile (80.0 mL) and heated to40° C. for 16 h. The resulting white precipitate was filtered, washedwith acetonitrile followed by hexanes and dried under vacuum to affordthe title compound (4.89 g, 14.95 mmol, 79% yield). MS (ESI) m/z 327.4[M]⁺, 329.5 [M+2]⁺.

B.6-(6-(2-Hydroxypropan-2-yl)pyridin-3-yl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

6-Bromo-4-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one(35.98 g, 110 mmol), 2-(5-(trimethylstannyl)pyridin-2-yl)propan-2-ol(See Example 5.E) (33.0 g, 110 mmol) and[1,1′-bis(diphenyl-phosphino)ferrocene]dichloro-palladium(II) complexwith dichloromethane (1:1) (8.05 g, 11.00 mmol) were combined in asealed tube and suspended in N,N-dimethylformamide (288 mL). Thereaction was then heated to 125° C. for 2 h. The reaction was cooledslightly and poured while still warm onto a silica gel column andpurified using an Biotage SP1 (0-100% (5% methanol in ethyl acetate) inhexanes). The desired fractions were combined and organic volatilesremoved under reduced pressure. The residue was triturated with 20%ethyl acetate in hexanes followed by several washes with denaturedethanol. The slightly yellow solid was dried under reduced pressure toafford the desired compound (15.08 g, 39.3 mmol, 35.8% yield). ¹H NMR(400 MHz, DMSO-d₆) δ (ppm) 11.32 (s, 1H), 9.07 (d, J=1.56 Hz, 1H), 8.29(dd, J=8.59, 2.34 Hz, 1H), 8.05 (s, 1H), 7.72 (d, J=8.20 Hz, 1H), 5.26(s, 1H), 4.21 (s, 2H), 3.83 (d, J=2.73 Hz, 2H), 3.51 (d, J=7.42 Hz, 2H),3.27 (t, J=11.32 Hz, 2H), 2.09 (br. s., 1H), 1.61 (d, J=11.3 Hz, 2H),1.46 (s, 6H), 1.24-1.38 (m, 2H); MS (ESI) m/z 384.2 [M+1]⁺; mp 268-269°C.

Example 177-(6-(2-Hydroxypropan-2-yl)pyridin-3-yl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

A.7-Bromo-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

Ethyl 2-(3,5-dibromopyrazin-2-ylamino)acetate (See Example 1.C) (1equiv), 2-methoxyethanamine (1 equiv), diisopropylethylamine (3 equiv),were suspended in dimethylsulfoxide and heated in an Emrys Biotagemicrowave reactor at 150° C. for 1 h. Standard ethyl acetate/water workup gave crude material, which was suspended in 99.7% acetic acid. Thereaction was sealed, heated to 120° C. and allowed to stir for 2 h. Thereaction was extracted in ethyl acetate. The organic layers were pooledand washed with saturated sodium bicarbonate, followed by brine anddried over magnesium sulfate. Concentration and flash columnchromatography (0-100% ethyl acetate in hexanes) gave the desiredproduct in 27% yield over two steps. MS (ESI) m/z 287.4 [M]⁺, 289.4[M+2]⁺.

B.7-(6-(2-Hydroxypropan-2-yl)pyridin-3-yl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

7-Bromo-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one(1 equiv), 2-(5-(trimethylstannyl)pyridin-2-yl)propan-2-ol (See Example5.E) (1 equiv) and dichlorobis(triphenylphosphine)-palladium(II) (0.2equiv) were suspended in dimethylformamide. The reaction was purged withnitrogen and was heated to 140° C. for 2 h. The reaction was cooled toroom temperature, filtered through Celite and washed with ethyl acetate.Volatiles were removed under reduced pressure and the resulting purpleslurry was purified using silica gel column chromatography (0-100% (5%methanol in ethyl acetate) in hexanes). The desired fractions werecombined and organic volatiles removed under reduced pressure. The solidwas triturated in 5% ethyl acetate in hexanes and washed with hexanes toafford the desired product in 38% yield. ¹H NMR (400 MHz, DMSO-d₆) δ(ppm) 9.02 (d, J=1.6 Hz, 1H), 8.27 (s, 1H), 8.24 (dd, J=8.6, 2.3 Hz,1H), 7.71 (d, J=0.8 Hz, 1H), 7.69 (s, 1H), 5.25 (s, 1H), 4.28 (t, J=6.2Hz, 2H), 4.20 (d, 2H), 3.60 (t, J=6.2 Hz, 2H), 3.26 (s, 3H), 1.46 (s,6H); MS (ESI) m/z 344.3 [M+1]⁺.

Example 187-(1H-Pyrrolo[2,3-b]pyridin-4-yl)-1-[2-(tetrahydro-pyran-4-yl)-ethyl]-3,4-dihydro-1H-pyrazino[2,3-b]pyrazin-2-one

A.7-(1H-Pyrrolo[2,3-b]pyridin-4-yl)-1-[2-(tetrahydro-pyran-4-yl)-ethyl]-3,4-dihydro-1H-pyrazino[2,3-b]pyrazin-2-one

A mixture of1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-7-(trimethylstannyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one(See Example 15.C) (1 equiv),4-bromo-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (1equiv), tris(dibezylideneacetone) palladium (0.13 equiv),tri-o-tolylphosphine (0.25 equiv) and triethylamine (2.8 equiv) inanhydrous dioxane was purged, degassed for 2 min and stirred at 95° C.under nitrogen for 3-4 h. Upon completion of the reaction as indicatedby TLC, the volatiles were removed under reduced pressure and theresidue was purified by column chromatography to give the desiredproduct in 35% yield. MS (ESI) m/z 479.7 [M+1]⁺. tert-Butyl4-(7-oxo-8-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylatewas stirred in methanolic hydrochloride solution at room temperature.Upon completion of the reaction as indicated by TLC, the solvent wasremoved under reduced pressure and the residue was purified on silicagel to give the title compound in 63% yield. ¹H NMR (DMSO-d₆, 400 MHz) δ(ppm) 11.72 (s, 1H), 8.38 (s, 1H), 8.25 (d, J=4.8 Hz, 1H), 7.79 (s, 1H),7.53-7.51 (m, 2H), 6.97 (q, J=1.6 Hz, 1H), 4.23 (s, 2H), 4.14 (t, J=7.6Hz, 2H), 3.81 (dd, J₁=2.4 Hz, J₂=11.2 Hz, 2H), 3.25 (d, J=10.8 Hz, 2H),1.67 (d, J=13.2 Hz, 2H), 1.61 (m, 3H), 1.22 (m, 2H); MS (ESI): m/z 379.2[M+1]⁺.

Example 191-(2-Methoxyethyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

A.1-(2-Methoxyethyl)-7-(trimethylstannyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

7-Bromo-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one(See Example 17.A) (0.5 g, 1.741 mmol), 1,1,1,2,2,2-hexamethyldistannane(0.856 g, 2.61 mmol) and tetrakis(triphenylphosphine) palladium(0)(0.201 g, 0.174 mmol) were combined in 1,4-dioxane (20 mL) and heated at140° C. for 2 h. The resulting mixture cooled to room temperature,diluted with ethyl acetate and filtered through Celite. The filtrate wasconcentrated under reduced pressure. Flash chromatography (0-30% ethylacetate in hexane) gave the desired product as clear oil (0.5 g, 1.34mmol, 77% yield). MS (ESI) m/z 373.0[M+2]⁺.

B.1-(2-Methoxyethyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

1-(2-Methoxyethyl)-7-(trimethylstannyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one(0.5 g, 1.348 mmol),3-bromo-2-methyl-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)pyridine(0.436 g, 1.348 mmol), tris(dibenzylidineacetone)dipalladium(0) (0.123g, 0.135 mmol), tri-o-tolylphosphine (0.082 g, 0.270 mmol),triethylamine (0.584 mL, 4.04 mmol) and N,N-dimethylformamide (10 mL)were combined in a 75 mL sealable flask, the atmosphere in the flask wasremoved and replaced with nitrogen. The mixture was stirred at 130° C.for 3 h. The resulting mixture was cooled to room temperature andfiltered. The organic layer was concentrated under reduced pressure. Theresulting residue was diluted with methanol and dimethylsulfoxide,filtered and purified using reverse-phase preparatory HPLC (10-30%acetonitrile+0.1% TFA in water+0.1% TFA, over 30 min). Fractionscontaining clean product were passed through a Phenomenex Strata-X-Csolid phase extraction column. The column was washed successively withwater, acetonitrile, methanol and 5% ammonium hydroxide in methanol. Theproduct eluted with the 5% ammonium hydroxide in methanol eluent and wasconcentrated under reduced pressure. The residue was triturated withethyl ether in hexane to make a fine powder and dried under vacuum at50° C. to give the desired product (0.05 g, 0.136 mmol, 10% yield) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 8.10 (br. s., 1H), 7.98(br. s., 1H), 7.94 (s, 1H), 7.73 (br. s., 1H), 4.13-4.28 (m, 4H), 3.55(t, J=6.25 Hz, 2H), 3.24 (s, 3H), 2.70 (br. s., 3H); MS (ESI) m/z367.2[M+1]⁺.

Example 206-(4-(4H-1,2,4-Triazol-3-yl)phenyl)-4-ethyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-onehydrochloride

A. 6-Bromo-4-ethyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

To a solution of 2-bromo-N-(3,5-dibromopyrazin-2-yl)acetamide (SeeExample 4.A) (1 equiv) and diisopropylethylamine (3 equiv) inacetonitrile was added ethanamine hydrochloride (1.05 equiv). Thesolution was allowed to heat to 70° C. for 30 min. The solution wascondensed under reduced pressure and purified using columnchromatography (0-75% ethyl acetate in hexanes) to afford the titlecompound in 36% yield. MS (ESI) m/z 257.5 [M]⁺, 259.4 [M+2]⁺.

B.4-Ethyl-6-(4-(4-(tetrahydro-2H-pyran-2-yl)-4H-1,2,4-triazol-3-yl)phenyl)-3,4-dihydro-pyrazino[2,3-b]pyrazin-2(1H)-one

6-Bromo-4-ethyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (1.1 equiv),4-(tetrahydro-2H-pyran-2-yl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4H-1,2,4-triazole(1 equiv) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane (0.05 equiv) were combined in 1,4-dioxane followedby the addition of sodium carbonate (3 equiv) in water. The solution washeated in a Biotage Emrys Optimizer microwave reactor to 120° C. for 30min. The solution was condensed under reduced pressure and purifiedusing column chromatography (0-10% methanol in ethyl acetate) to affordthe title compound in 45% yield. MS (ESI) m/z 406.6 [M+1]⁺.

C.6-(4-(4H-1,2,4-Triazol-3-yl)phenyl)-4-ethyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-onehydrochloride

4-Ethyl-6-(4-(4-(tetrahydro-2H-pyran-2-yl)-4H-1,2,4-triazol-3-yl)phenyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-onein ethanol was treated with 2 N hydrogen chloride in dioxane. Thesolution was stirred at 75° C. for 1 h. The solution was condensedpartially and cooled. Cold ethanol was added to the slurry and theresulting precipitate filtered and washed with additional cold ethanolfollowed by hexanes to afford the title compound as the hydrochloridesalt in 82% yield. ¹H NMR (400 MHz, METHANOL-d₄) δ (ppm) 9.18 (s, 1H),8.22 (d, J=8.59 Hz, 2H), 8.04-8.09 (m, 3H), 7.66-7.74 (m, 1H), 7.58-7.64(m, 1H), 4.24 (s, 2H), 3.74 (q, J=7.03 Hz, 2H), 1.29 (t, J=7.03 Hz, 4H),0.79-0.98 (m, 4H); MS (ESI) m/z 322.2 [M+1]⁺.

Building Block Synthesis

The following building blocks were prepared and used in the preparationsas described herein, or variations known in the art thereof

tert-Butyl 4-bromo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

A. 4-Bromo-1H-pyrrolo[2,3-b]pyridine

A solution of trifluoromethyl sulfonic anhydride (9.3 g, 33 mmol) wasadded dropwise to a mixture of 1H-pyrrolo[2,3-b]pyridine 7-oxide (3 g,22 mmol) and tetrabutyl ammonium bromide (10.8 g, 33 mmol) inN,N-dimethylformamide (30 mL) at 0° C. The resulting mixture was stirredat 0° C. for 4 h and at room temperature overnight. The reaction wasquenched with water and neutralized with 1N sodium hydroxide to pH=7.The resulting mixture was extracted twice with a mixture of methylenechloride and i-propanol (30 mL, V_(m):V_(p)=4:1). The organic layer wascombined, dried over anhydrous sodium sulfate, concentrated and purifiedby a reverse-phase preparatory HPLC (0-30%: acetonitrile+0.1% TFA inwater+0.1% TFA, over 15 min.) to give the title compound (1.5 g, 34.3%yield). MS (ESI) m/z 196.8 [M+1]⁺, 198.8 [M+3]⁺.

B. tert-Butyl-4-bromo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

A mixture of 4-bromo-1H-pyrrolo[2,3-b]pyridine (250 mg, 1.26 mmol),di-tert-butyl dicarbonate (302 mg, 1.38 mmol),dimethyl-pyridin-4-yl-amine (7.6 mg, 0.06 mmol) and triethylamine (127mg, 1.26 mmol) in anhydrous methylene chloride (15 mL) was stirred atroom temperature for 3 h. Upon completion of the reaction as indicatedby TLC, the volatiles were removed under reduced pressure and theresidue was purified by column chromatography on silica gel (9-25% ethylacetate in petroleum ether) to give the desired product (230 mg, 61%yield) as an oil. MS (ESI) m/z 242.9 [M−56+1]⁺

1-(Tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

A. 4-Bromo-1H-indazole

To a solution of 3-bromo-2-methylaniline (5 g, 27 mmol) in chloroform (1mL) was added acetic anhydride (5 g, 27 mmol) at 0° C. and the mixturewas stirred at room temperature for 1 h. Potassium acetate (0.75 g, 7.8mmol) and isoamyl nitrite (0.78 g, 58 mmol) were added and the reactionmixture was refluxed for 18 h. The volatiles were removed under reducedpressure and water (0.65 mL) was added. The mixture was concentrated,diluted with concentrated hydrochloride acid (1 mL) and heated at 50° C.for 2 h. After being cooled to room temperature, aqueous sodiumhydroxide solution (50%) was added until pH=10. The aqueous mixture wasextracted with ethyl acetate (100 mL×3). The combined organic layer waswashed with brine (150 mL), dried over anhydrous sodium sulfate,filtered, evaporated and purified on silica gel column (3% ethyl acetatein petroleum ether) to give the desired product (2.69 g, 34% yield) as asolid. MS (ESI): m/z 197.0 [M+1]⁺.

B. 4-Bromo-1-(tetrahydro-pyran-2-yl)-1H-indazole

A solution of 4-bromo-1H-indazole (1.82 g, 9.24 mmol),3,4-dihydro-2H-pyran (1.55 g, 18.48 mmol) and toluene-4-sulfonic acid(0.26 g, 1.39 mmol) in anhydrous tetrahydrofuran (40 mL) was heated at80° C. overnight under nitrogen. The solvent was removed under reducedpressure and the residue was purified on silica gel column (3% ethylacetate in petroleum ether) to give the title compound (2.13 g, 81%yield) as a yellow solid. MS (ESI): m/z 280.9 [M+1]⁺.

C.1-(Tetrahydro-pyran-2-yl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-Indazole

A degassed mixture of 4-bromo-1-(tetrahydro-pyran-2-yl)-1H-indazole(2.13 g, 7.45 mmol), bis(pinacolato)diboron (3.73 g, 14.9 mmol),potassium phosphate (2.70 g, 12.67 mmol), palladium acetate (0.174 g0.75 mmol) and triphenylphosphine (0.59 g, 2.24 mmol) in1,2-dimethoxy-ethane (50 mL) was heated at 100° C. under nitrogenovernight. After cooling to room temperature, the reaction mixture wasfiltered, concentrated under reduced pressure and purified on silica gelcolumn (10-30% ethyl acetate in petroleum ether) to give the product(1.83 g, 74% yield) as a solid. MS (ESI): m/z 329.2 [M+1]⁺.

3-(4-Bromo-2-fluoro-3-methylphenyl)-4-(tetrahydro-2h-pyran-2-yl)-4H-1,2,4-triazole

A. 4-Bromo-3-fluoro-2-methylaniline

To a stirred solution of 3-fluoro-2-methylaniline (25 g, 200 mmol) inacetic acid (140 mL) at 0-5° C. was added hydrogen bromide (100 mL, 200mmol) then dimethyl sulfoxide (72 mL) was added slowly dropwise(reaction is exothermic and at temperature higher than 5-15° C. producesdibromoisomer). The mixture was stirred at 5-15° C. for 12 h (mixturebecame clear solution). The resulting solution was cooled to 0° C. andneutralized with sodium hydroxide then with sodium bicarbonate to pH 7.The mixture was extracted with ethyl acetate. The organic layer wasconcentrated under reduced pressure. Flash chromatography (0-10% ethylacetate in hexane) gave the desired product as a white solid (23.3 g,114 mmol, 57% yield). ¹H NMR (400 MHz, CHLOROFORM-d) δ (ppm) 7.11 (t,J=8.20 Hz, 1H), 6.35 (d, J=8.98 Hz, 1H), 3.72 (br. s., 2H), 2.07 (d,J=1.95 Hz, 3H).

B. 4-Amino-2-fluoro-3-methylbenzonitrile

A mixture of 4-bromo-3-fluoro-2-methylaniline (23 g, 113 mmol) andcyanocopper (20.19 g, 225 mmol) N,N-dimethylformamide (200 mL) washeated to 140° C. for 7 h. After the mixture was cooled to roomtemperature filtered and poured into a separatory funnel containingwater and ethyl acetate (1:1). Layers were separated and the organiclayer was concentrated under reduced pressure. Flash chromatography(0-50% ethyl acetate in hexane) gave the desired product (11.4 g, 76mmol, 67% yield) as a brown solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ(ppm) 7.22 (t, 1H), 6.45 (d, J=8.59 Hz, 1H), 4.23 (br. s., 2H), 2.07 (s,3H); MS (ESI) m/z 151.1[M+1]⁺.

C. 4-Bromo-2-fluoro-3-methylbenzonitrile

A mixture of dimethyl sulfoxide (400 mL) and potassium nitrite (22.67 g,266 mmol) was stirred to dissolve potassium nitrite and4-amino-2-fluoro-3-methylbenzonitrile (10 g, 66.6 mmol) and copper(I)bromide (1.911 g, 13.32 mmol) were added. Aqueous 48% hydrogen bromide(33 mL, 266 mmol), diluted with dimethyl sulfoxide (200 mL), was addeddropwise and the reaction stirred for 2 h. After complete conversion ofstarting material, the reaction mixture was poured into iced-cold waterand neutralized to pH 7 with cold concentrated sodium hydroxide. Theresulting solid was collected by filtration to give the desired product(11.4 g, 53.3 mmol, 80% yield) as white solid. ¹H NMR (400 MHz,CHLOROFORM-d) δ (ppm) 7.47 (d, J=9.37 Hz, 1H), 7.33 (t, 1H), 2.39 (d,J=2.34 Hz, 3H).

D. 4-Bromo-2-fluoro-3-methylbenzamide

4-Bromo-2-fluoro-3-methylbenzonitrile (11 g, 51.4 mmol) in a 100 mLmixture of TFA-sulfuric acid (4:1, V/V) was stirred at 40° C. for 16 h.After complete conversion of starting material, the reaction mixture waspoured into iced-cold water. The resulting solid was filtered off andwashed with water and dried to give the desired product (11.24 g, 48.4mmol, 94% yield) as a white solid. MS (ESI) m/z 234.1 [M+2]⁺.

E. 3-(4-Bromo-2-fluoro-3-methylphenyl)-1H-1,2,4-triazole

4-Bromo-2-fluoro-3-methylbenzamide (11 g, 47.4 mmol) andN,N-dimethylformamide dimethylacetal (60 mL) were combined in a 100 mLround-bottom flask with a stir bar and heated at 55° C. under a refluxcondenser under nitrogen for 3 h. The resulting mixture was concentratedunder reduced pressure and dried under vacuum to give yellow oil, whichwas used in the next step without purification. The residue was dilutedwith acetic acid (60 mL) at 0° C. and hydrazine monohydrate (20 mL) wasadded dropwise and allowed to stirred at rt for 5 h. After completeconversion of starting material, the reaction mixture was poured intoiced-cold water and neutralized to pH 7 with ice cold concentratedsodium hydroxide. The resulting solids were collected by vacuumfiltration. Solid was dissolved in ethyl acetate (400 mL) and stirredfor 15 min, filtered the insoluble solid, the filtrate dried overmagnesium sulfate, filtered, concentrated under reduced pressure anddried under vacuum to give a brown pure solid (4.3 g, 16.79 mmol, 35%yield) which was used in the next step without purification. ¹H NMR (400MHz, CHLOROFORM-d) δ (ppm) 8.12 (s, 1H), 7.97 (t, J=8.00 Hz, 1H), 7.52(d, J=8.59 Hz, 1H), 2.44 (d, 3H).

F.3-(4-Bromo-2-fluoro-3-methylphenyl)-4-(tetrahydro-2H-pyran-2-yl)-4H-1,2,4-triazole

Methanesulfonic acid (0.090 mL, 1.390 mmol) was added to a stirredsolution of 3-(4-bromo-2-fluoro-3-methylphenyl)-1H-1,2,4-triazole (7.0g, 27.3 mmol) and 3,4-dihydro-2H-pyran (12.68 mL, 139 mmol) intetrahydrofuran (33 mL). The resulting mixture stirred at 85° C. under areflux condenser under nitrogen for 20 h. The mixture was diluted withethyl acetate and washed with saturated aqueous sodium bicarbonate andbrine. The organic layer was dried over magnesium sulfate, filtered andconcentrated under reduced pressure. The residue was purified usingflash chromatography (20-30-50% ethyl acetate in hexane). Productcontaining fractions were combined and solvent removed under reducedpressure to afford desired product (8.8 g, 95% yield) as a yellow solid.MS (ESI) m/z 340.0 [M]⁺

3-(4-Bromo-2-fluorophenyl)-4h-1,2,4-triazole

A. 4-Bromo-2-fluorobenzamide

A solution of 4-bromo-2-fluorobenzonitrile (10.0 g, 50.0 mmol) in a 70mL mixture of TFA (56.0 mL, 727 mmol)-sulfuric acid (14.0 mL, 263 mmol)(4:1 V/V) was stirred at 40° C. for 16 h. The reaction was poured whilestill warm over ice water. The product precipitated and the solid wasfiltered and dried to give 4-bromo-2-fluorobenzamide (9.53 g, 43.7 mmol,87% yield) as a white solid. MS (ESI) m/z 218.1 [M]⁺, 220.1 [M+2]⁺.

B. 3-(4-Bromo-2-fluorophenyl)-4H-1,2,4-triazole

4-Bromo-2-fluorobenzamide (9.53 g, 43.7 mmol) and N,N-dimethylformamidedimethylacetal (75.0 mL) were combined in a 500 mL round bottom flaskand purged with nitrogen. The reaction was heated to reflux at 85° C.for 2 h. The resulting mixture was concentrated under reduced pressureand dried under vacuum to afford a yellow oil. The oil was suspended inconcentrated acetic acid (75.0 mL) and cooled to 0° C. Hydrazine hydrate(21.88 g, 437 mmol) was added dropwise and the mixture was allowed tostir at rt for 5 h. The reaction was poured warm onto cold ice andextracted with dichloromethane (3×200 mL). Organic volatiles wereremoved under reduced pressure to afford3-(4-bromo-2-fluorophenyl)-4H-1,2,4-triazole (7.20 g, 29.7 mmol, 68.1%yield) as a white solid. MS (ESI) m/z 241.9 [M]⁺, 243.9 [M+2]⁺.

2-(4-Methyl-5-(trimethylstannyl)pyridin-2-yl)propan-2-ol

A. 2-(5-Bromo-4-methylpyridin-2-yl)propan-2-ol

2,5-Dibromo-4-methylpyridine (4.0 g, 15.94 mmol) was dissolved intoluene (60.0 mL) and the reaction was cooled to −78° C. Butyllithium(7.01 mL, 17.54 mmol) was added dropwise and the reaction was allowed tostir for 30 min. Acetone (4.69 mL, 63.8 mmol) was then added and thereaction was allowed to warm to rt and stir for 16 h. The reaction wasquenched with saturated ammonium chloride, extracted into ethyl acetate(3×200 mL) and washed with water followed by brine. The organics weredried over magnesium sulfate and volatiles removed under reducedpressure. The compound was purified on silica gel chromatography (0-50%ethyl acetate in hexanes) to afford2-(5-bromo-4-methylpyridin-2-yl)propan-2-ol (2.33 g, 10.13 mmol, 63.5%yield). MS (ESI) m/z 230.3 [M]⁺, 232.3 [M+2]⁺.

B. 2-(4-Methyl-5-(trimethylstannyl)pyridin-2-yl)propan-2-ol

2-(5-Bromo-4-methylpyridin-2-yl)propan-2-ol (2.33 g, 10.13 mmol) andtetrakis(triphenylphosphine)palladium(0) (1.045 g, 1.013 mmol) wereadded to a pressure tube and suspended in 1,4-dioxane (33.8 mL).1,1,1,2,2,2-Hexamethyldistannane (2.99 mL, 12.15 mmol) was then addedand heated to 150° C. for 30 min. The reaction was allowed to cool to rtand was filtered through celite and washed with ethyl acetate. Organicvolatiles were removed under reduced pressure followed by an extractionin ethyl acetate (3×200 mL) and water. Organic volatiles were removedunder reduced pressure and the compound purified using silica gel columnchromatography on an Biotage column (10-50% ethyl acetate in hexanes) toafford 2-(4-methyl-5-(trimethylstannyl)pyridin-2-yl)propan-2-ol (1.75 g,5.57 mmol, 55.0% yield). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 8.31 (s, 1H),7.51 (s, 1H), 5.25 (br. s., 1H), 2.37 (s, 3H), 1.41 (s, 6H), 0.65 (br.s., 3H), 0.34 (s, 6H).

Tert-butyl3-(5-bromo-6-methylpyridin-2-yl)-1H-1,2,4-triazole-1-carboxylate

A. 5-Bromo-6-methylpicolinonitrile

A 1-L, three-neck, round-bottom flask equipped with a mechanical stirrerand a nitrogen inlet was charged with 3,6-dibromo-2-methylpyridine (150g, 0.59 mol), copper (I) cyanide (42.8 g, 0.47 mol) and sodium cyanide(23 g, 0.47 mol). To the mixture was added N,N-dimethylformamide (300mL). The mixture was heated to 95° C. and stirred for 48 h. The reactionmixture was cooled to ambient temperature and poured into ethanol (3 L)while stirring. The mixture was filtered through a pad of Celite, thefiltrate was concentrated under reduced pressure and partitioned betweenwater (3 L) and ethyl acetate (3 L). The organic layer was separated andwashed with brine (2×600 mL), dried over anhydrous sodium sulfate,filtered and concentrated. The crude product was purified by silica gelplug purification (0-5% ethyl acetate in hexanes) to afford the product(61.5 g, 45% yield) as a white solid. In addition, 19.32 g (14%) of themixture of the starting material and the product was isolated.

B. 5-Bromo-6-methylpicolinohydrazonamide

A 500-mL, three-neck, round-bottom flask was equipped with5-bromo-6-methylpicolinonitrile (101.5 g, 0.515 mol), ethanol (122 mL)and hydrazine hydrate (50 mL, 1.03 mol). The resulting very thickmixture was allowed to stir at ambient temperature for 24 h. Moreethanol (50 mL) was added and the mixture was allowed to stir over theweekend. The mixture was filtered and washed with cold ethanol (100 mL)and cold hexanes (50 mL). The solids were dried in a vacuum oven toafford the product (110 g, 93% yield) as an off-white solid.

C. 3-Bromo-2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridine

A 500-mL, three-neck, round-bottom flask was equipped with a mechanicalstirrer, a thermocouple connected to a J-KEM temperature controller anda reflux condenser. The flask was charged with5-bromo-6-methylpicolinohydrazonamide (100 g, 0.463 mol) and formic acid(250 mL). The resulting solution was heated to 100° C. and stirred for48 h. Formic acid was removed under reduced pressure and the resultingslurry was treated with water (1.5 L) while vigorously stirring. Themixture was filtered and washed with water (300 mL). The solids weretransferred into a round-bottom flask and treated with water (1 L) and 1M sodium hydroxide solution until pH 7. The mixture was allowed to stirfor 30 min, filtered, washed with water (300 mL) and dried in a vacuumoven at 30-35° C. for 48 h to afford the product (96 g, 92% yield) as awhite solid.

D.3-Bromo-2-methyl-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)pyridine

To a suspension of 3-bromo-2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridine(96.0 g, 0.4 mol) in tetrahydrofuran (780 mL) was added3,4-dihydro-2H-pyran (72.5 mL, 0.8 mol) and methanesulfonic acid (3.2mL). The mixture was heated to 65° C. and the resulting yellow solutionwas allowed to stir at 65° C. for 6 h. The mixture was cooled to ambienttemperature, quenched with triethylamine (23 mL), concentrated underreduced pressure and further dried in a high vacuum for 1 h. Theresulting oil was dissolved in acetonitrile (250 mL) and the solutionwas added into water (750 mL) while stirring vigorously. Moreacetonitrile (80 mL) was added and the mixture was allowed to stir for 1h. The resulting solids were filtered, washed with 1:4acetonitrile/water (800 mL) and dried in a vacuum oven for 48 h toafford the product (110 g, 85% yield) as a white solid. The product wasfurther purified by silica gel plug purification (1:1 hexanes/ethylacetate) to give 88 g of the pure product as a white solid and 16.2 g ofless pure product. MS (ESI) m/z 239.1 [M]⁺, 241.1 [M+2]⁺.

E. tert-Butyl3-(5-bromo-6-methylpyridin-2-yl)-1H-1,2,4-triazole-1-carboxylate

To a mixture of 3-bromo-2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridine (300g, 1.25 mol) in dioxane (4 L) was added sodium carbonate (398 g, 3.75mol), followed by water (4 L). di-tert-Butyl dicarbonate (274 g, 1.25mol) was added and the mixture was stirred of 1 h at room temperature.The mixture was then diluted with cold water (˜10 L) and extracted withethyl acetate (4 L×3). The combined ethyl acetate layer was washed withbrine, dried over sodium sulfate, filtered and concentrated to affordthe product (254 g, 60% yield) as a slightly yellow solid.

4-(Tetrahydro-2H-pyran-2-yl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4h-1,2,4-triazole

A. Ethyl 4-bromobenzimidate hydrochloride

A solution of 4-bromobenzonitrile (17.65 g, 97 mmol) in ethanol (500 mL)was acidified with hydrogen chloride gas at 0° C. for fifteen minutes.The solution was allowed to stir for 16 h. The solution was condensedunder reduced pressure to afford the title compound (25.35 g, 99%). MS(ESI) m/z 228.1 [M]⁺, 230.4 [M+2]⁺.

B. 3-(4-Bromophenyl)-4H-1,2,4-triazole

Ethyl 4-bromobenzimidate hydrochloride (35.6 g, 135 mmol), formichydrazide (16.16 g, 269 mmol) and triethylamine (75 mL, 538 mmol) werecombined in a screw capped flask and heated to 85° C. for 16 h. Thesolution was condensed under reduced pressure to afford a solid, whichwas partitioned between water and ethyl acetate (3×), dried overmagnesium sulfate and solvent removed under reduced pressure. Theresulting solid was sonicated with 20% ethyl acetate in hexanes,filtered and dried to afford the title compound (14.6 g, 65.2 mmol, 48%yield). MS (ESI) m/z 224.1 [M]⁺, 226.1 [M+2]⁺.

C. 3-(4-Bromophenyl)-4-(tetrahydro-2H-pyran-2-yl)-4H-1,2,4-triazole

A solution of 3-(4-Bromophenyl)-4H-1,2,4-triazole (14.1 g, 62.9 mmol),3,4-dihydro-2H-pyran (10.59 mmol) and methanesulfonic acid (1.19 g, 6.29mmol) in tetrahydrofuran (150 mL) was heated at 75° C. for 2 h. Thesolution was condensed and partitioned between sodium bicarbonatesolution and ethyl acetate (3×), the organics dried over magnesiumsulfate, filtered and solvent removed under reduced pressure. The solidwas triturated with 10% ethyl acetate in hexanes to afford the titlecompound (8.1 g, 26.3 mmol, 70% yield). MS (ESI) m/z 308.4 [M]⁺, 310.5[M+2]⁺.

D.4-(Tetrahydro-2H-pyran-2-yl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4H-1,2,4-triazole

3-(4-Bromophenyl)-4-(tetrahydro-2H-pyran-2-yl)-4H-1,2,4-triazole (8.1 g,26.3 mmol), bis(pinacolato)diboron (6.67 g, 26.3 mmol) and potassiumacetate (10.32 g, 105 mmol) were combined in dimethylformamide (100 mL).The solution was purged with nitrogen gas for 2 minutes.Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane (1.07 g, 1.31 mmol) was then added and the solutionheated to 100° C. for 16 h. The solution was filtered through celite andthe filtrate condensed under reduced pressure to afford a dark oil. Theoil was purified via Biotage chromatography (0-70% ethyl acetate inhexanes) to afford a solid upon drying. The solid was diluted withhexanes, sonicated, filtered and dried to afford the title compound (7.1g, 20.0 mmol, 71% yield). MS (ESI) m/z 356.5 [M+1]⁺.

5-Bromo-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)pyridine

A. (E)-5-bromo-N-((dimethylamino)methylene)picolinamide

A solution of 5-bromopicolinamide (0.500 g, 2.49 mmol) anddimethylformamide dimethylacetal (20 mL), were heated to 85° C. for 3 h.The reaction was concentrated and the product was used directly in thenext step (0.604 g, 95% yield). MS (ESI) m/z 257.1 [M+1]⁺.

B. 5-Bromo-2-(1H-1,2,4-triazol-3-yl)pyridine

A solution of (E)-5-bromo-N-((dimethylamino)methylene)picolinamide(0.604 mg, 2.36 mmol) and hydrazine (2.12 g, 66.1 mmol) was stirred at25° C. for 3 h. The reaction was concentrated and diluted with water.The resulting precipitate was collected by filtration and dried undervacuum to give the title compound (0.442 g, 83% yield). MS (ESI) m/z226.1 [M+1]⁺.

C.5-Bromo-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)pyridine

A solution of 5-bromo-2-(1H-1,2,4-triazol-3-yl)pyridine (0.342 mg, 1.52mmol), 3,4-dihydro-2H-pyran (0.256 g, 3.04 mmol) and4-methylbenzenesulfonic acid (0.058 g, 0.30 mmol) in tetrahydrofuran washeated to 75° C. for 6 h. The reaction was concentrated and purifiedusing Biotage column chromatography (0-20% methanol in dichloromethane)to provide semi-clean product as an oil (0.614 g, 1.9 mmol, >100%yield). This material was used without further purification. MS (ESI)m/z 309.4 [M]⁺, 311.1 [M+2]⁺.

tert-Butyl6-bromo-4-methyl-2-(methylamino)-1H-benzo[d]imidazole-1-carboxylate

A. (6-Bromo-4-methylbenzimidazol-2-yl)-N-methylamine

Isothiocyanatomethane (0.055 g, 0.746 mmol) in N,N-dimethylformamide(1.0 mL) was added dropwise slowly to a stirred solution of5-bromo-3-methylbenzene-1,2-diamine (0.150 g, 0.746 mmol) inN,N-dimethylformamide (1.5 mL) at 0° C. The cold bath was removed, thereaction mixture was capped and stirred at room temperature for 48 h.N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.157 g,0.821 mmol) was added and the reaction mixture capped and heated at 40°C. overnight. The resulting mixture was diluted with methanol, filteredand purified using reverse-phase preparatory HPLC (10-50%acetonitrile+0.1% TFA in H₂O+0.1% TFA, over 30 min). Fractionscontaining the desired product were combined and most of the solventremoved under reduced pressure. Acetonitrile was added and the resultingmixture loaded on a Strata ion exchange column. The column was washedsuccessively with water, acetonitrile, methanol and 5% ammoniumhydroxide in methanol. The product eluted with the 5% ammonium hydroxidein methanol and was concentrated under reduced pressure and dried underhigh vacuum to give the desired product (0.128 g, 0.53 mmol, 72% yield)as a slightly yellow waxy solid. MS (ESI) m/z 240 [M]⁺, 242 [M+2]⁺.

B. tert-Butyl6-bromo-4-methyl-2-(methylamino)-1H-benzo[d]imidazole-1-carboxylate

(6-Bromo-4-methylbenzimidazol-2-yl)-N-methylamine (0.128 g, 0.533 mmol),diisopropylethylamine (0.464 mL, 2.67 mmol), di-tert-butyl dicarbonate(0.349 g, 1.599 mmol) and N,N-dimethylformamide (5 mL) were combined ina 100 mL round bottom flask, capped and stirred at room temperature for21 h. The resulting mixture was partitioned between water and ethylacetate. The layers were separated and the organics were washed withwater and brine. The organics were dried over magnesium sulfate,filtered, concentrated under reduced pressure and purified using flashchromatography (10-30% ethyl acetate in hexanes) to give the desiredproduct (0.092 g, 0.27 mmol, 51% yield) as a yellow waxy solid. MS (ESI)m/z 340 [M]⁺, 342 [M+2]⁺.

Tert-butyl6-bromo-4-methyl-2-(methylamino)-1H-benzo[d]imidazole-1-carboxylate

A.7-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-amine

3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene-1,2-diamine(See Example 1.G) (500 mg, 2.015 mmol) and cyanic bromide (0.484 mL,2.418 mmol) were added to a round bottom flask at room temperature,suspended in methanol (10.0 mL) and allowed to stir for 1.5 h. Volatileswere removed under reduced pressure followed by the addition ofsaturated sodium bicarbonate. The precipitate was collected viafiltration, washed with ethyl acetate and dried under reduced pressureto afford the title compound (557 mg, 2.039 mmol, quant. yield).Compound was carried forward without further purification orcharacterization. MS (ESI) m/z 273.8 [M+1]⁺.

tert-Butyl6-bromo-4-methyl-2-(methylamino)-1H-benzo[d]imidazole-1-carboxylate

A. 6-Bromo-4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazole

6-Bromo-4-methyl-1H-benzo[d]imidazole (1.02 g, 4.83 mmol) was dissolvedin tetrahydrofuran (10 mL) at room temperature with stirring undernitrogen. 3,4-Dihydro-2H-pyran (3.5 mL, 38.4 mmol) and methanesulfonicacid (0.032 mL, 0.48 mmol) were added and the resulting mixture heatedat 75° C. for 49 h. The resulting mixture was cooled to roomtemperature, diluted with ethyl acetate and washed with saturatedaqueous sodium bicarbonate and brine. The organics were dried overmagnesium sulfate, filtered and concentrated under reduced pressure.Flash chromatography (50-100% ethyl acetate in hexanes) gave the desiredproduct (1.32 g, 4.47 mmol, 93% yield) as a light yellow solid. MS (ESI)m/z 295.1 [M]⁺, 297.3 [M+2]⁺.

B.4-Methyl-1-(tetrahydro-2H-pyran-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole

6-Bromo-4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazole(1.320 g, 4.47 mmol), bis(pinacolato)diboron (1.192 g, 4.70 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (183 mg, 0.22 mmol), potassium acetate (1.317g, 13.4 mmol) and dimethyl sulfoxide (9 mL) were combined in a roundbottom flask and stirred. The atmosphere in the flask was removed undervacuum and replaced with nitrogen three times. The resulting mixture washeated at 90° C. under nitrogen for 1.5 h. The resulting mixture wasdiluted with ethyl acetate and filtered through Celite. The filter cakewas washed thoroughly with ethyl acetate. The filtrate was washed twicewith water, once with brine, dried over magnesium sulfate, filtered andconcentrated on a under reduced pressure. Flash chromatography (50-100%ethyl acetate in hexanes) gave the desired product at ˜90% purity (1.31g, 3.83 mmol, 77% yield) as a yellow tan foam-solid. MS (ESI) m/z 343.2[M+1]⁺.

5.2 BIOLOGICAL EXAMPLES 5.2.1 Biochemical Assays

mTOR HTR-FRET Assay.

The following is an example of an assay that can be used to determinethe mTOR inhibitory activity of a test compound. Heteroaryl Compoundswere dissolved in DMSO and prepared as 10 mM stocks and dilutedappropriately for the experiments. Reagents were prepared as follows:

“Simple TOR buffer” (used to dilute high glycerol TOR fraction): 10 mMTris pH 7.4, 100 mM NaCl, 0.1% Tween-20, 1 mM DTT. Invitrogen mTOR (cat#PR8683A) was diluted in this buffer to an assay concentration of 0.200μg/mL.

ATP/Substrate solution: 0.075 mM ATP, 12.5 mM MnCl₂, 50 mM Hepes, pH7.4, 50 mM β-GOP, 250 nM Microcystin LR, 0.25 mM EDTA, 5 mM DTT, and 3.5μg/mL GST-p70S6.

Detection reagent solution: 50 mM HEPES, pH 7.4, 0.01% Triton X-100,0.01% BSA, 0.1 mM EDTA, 12.7 μg/mL Cy5-αGST Amersham (Cat #PA92002V), 9ng/mL α-phospho p70S6 (Thr389) (Cell Signaling Mouse Monoclonal #9206L),627 ng/mL α-mouse Lance Eu (Perkin Elmer Cat #AD0077).

To 20 μL of the Simple mTor buffer is added 0.5 μL of test compound inDMSO. To initiate the reaction 5 μL of ATP/Substrate solution was addedto 20 μL of the Simple TOR buffer solution (control) and to the compoundsolution prepared above. The assay was stopped after 60 min by adding 5μL of a 60 mM EDTA solution; 10 μL of detection reagent solution wasthen added and the mixture was allowed to sit for at least 2 hoursbefore reading on a Perkin-Elmer Envision Microplate Reader set todetect LANCE Eu TR-FRET (excitation at 320 nm and emission at 495/520nm).

PI3K Alpha and Gamma Assays.

PI3K alpha and gamma assays were run using the procedures described inthe Millipore PI3K assay kit (cat #33-017). PI3K alpha and gamma enzymewere obtained from Invitrogen (Cat # PV4788 and PV4786).

Selected Heteroaryl Compounds have, or are expected to have, an IC₅₀below 10 μM in this assay, with some compounds having an IC₅₀ below 1μM, and others having an IC₅₀ below 0.10 μM.

DNA-PK Assay.

DNA-PK assays were performed using the procedures supplied in thePromega DNA-PK assay kit (catalog #V7870). DNA-PK enzyme was purchasedfrom Promega (Promega cat #V5811).

Selected Heteroaryl Compounds have, or are expected to have, an IC₅₀below 10 μM in this assay, with some compounds having an IC₅₀ below 1μM, and others having an IC₅₀ below 0.10 μM.

5.2.2 Cell-Based Assays

PC-3 p-S6 and p-Akt MesoScale Assay.

The following is an example of an assay that can be used to determinethe anticancer activity of a test compound. PC-3, a prostateadenocarcinoma cell line (#CRL-1435) was used in the pS6 MesoscaleAssay. The cells were grown in F-12 Kaighns' supplemented with 10% FetalBovine Serum and 1% Penicillin/Streptomycin. The following buffers wereused: Complete Tris Lysis Buffer (for 10 mL use: 100 μL phosphataseinhibitor I (100× stock), 100 μL phosphatase inhibitor II (100× stock),1 tablet Complete Mini (EDTA-free), 40 μL PMSF, all mixed thoroughly for5 minutes at room temperature); 1× Tris wash Buffer (for 250 mL use: 25mL 10× Tris wash buffer, 225 mL deionized water, store at roomtemperature); MSD blocking solution-A (for 20 mL use: 20 mL 1× tris washbuffer and 600 mg MSD blocker A, store on ice); Antibody dilution buffer(for 3 mL use: 1 mL blocking solution-A, 1.82 mL 1× tris wash buffer,150 μL 2% MSD blocker D-M, 30 μL 10% MSD blocker D-R, store on ice).

On day one in the afternoon, cells were plated in 96-well flat bottomcell culture plates at 20,000 cells/well in 180 μL of volume. On day 2in the morning, test compounds were diluted to the desired concentrationand added to the cells. Cells were treated with compound for 1 hour at37° C., 5% CO₂. The media was removed carefully and 50 μL 1× Tris LysisBuffer was added to each well and the plate placed on a shaker at 4° C.for 1 hour to lyse the cells. 35 μL of lysate from each well was used toassay for p-S6 levels using the protocol described in the manual forMA6000 Phospho-S6RP (Ser235/236) Whole Cell Lysate Kit #K110DFD-3. Thelysate was assayed for p-Akt levels using the protocol described in themanual for MA6000 Phospho-Akt (Ser4730 whole cell lysate Kit(#K111CAD-3). The plate was read on Sector Imager plate reader. IC₅₀values were calculated from dose response curves.

Heteroaryl Compounds have, or are expected to have, an IC₅₀ below 10 μMin this assay, with some compounds having an IC₅₀ below 1 μM, and othershaving an IC₅₀ below 0.10 μM.

Btk-PH, Akt-PH and FoxO-EGFP Translocation Assays.

The following is an example of an assay that can be used to determinethe anticancer activity of a test compound. BTK-PH_CHO cells (BioimageC007A) were grown in Nut.MixF-12-Ham supplemented with 10% Fetal BovineSerum, 1% Penicillin/Streptomycin, 0.5 mg/mL Geneticin and 0.25% DMSO.The cells were plated at 12,000 cells per well in a black wall clearbottom 96-well plate. Following 24 hour incubation, the cells werewashed with cell wash buffer and incubated for 1 hour with cell washbuffer. Cells were then treated with control/test compounds and IGF-1(insulin-like growth factor-1) for 4 minutes at room temperature. Thecells were then fixed, washed and stained with Hoescht in PBS containing0.5% Triton X-100. Plates were sealed and then read on Cellomics after30 minutes. Akt-PH_CHO cells (Bioimage C006A) were grown in the samemedia as the BTK-PH_CHO cells. The cells were plated at 10,000 cells perwell in a black clear bottom 96-well plate. The rest of the protocol wasidentical to the Btk-PH assay (as above). U-2 OS cell lines stablytransfected with FoxO-EGFP construct was a gift from Gary Chiang,Burnham Institute, La Jolla. The cells were grown in DMEM supplementedwith 10% Fetal Calf Serum and 1% Penicillin/Streptomycin. The cells wereplated at 20,000 cells per well in a black clear bottom 96-well plate.Following overnight incubation, the cells were treated with control/testcompounds and incubated for 2 hours. The cells were fixed, washed andstained with Hoescht. The plates were then washed with PBS three timesand then 100 μL PBS was added to each well. The plate was then coveredwith a transparent cover slip. The plate was read on Cellomics and theIC₅₀ values were calculated compared to Wortmannin.

Selected Heteroaryl Compounds have, or are expected to have, an IC₅₀below 30 μM in this assay, with some compounds having an IC₅₀ below 1μM, and others having an IC₅₀ below 0.10 μM.

Cell Proliferation Assay.

The following is an example of an assay that can be used to determinethe anticancer activity of a test compound. The assay was used toquantify cell proliferation based on measurement of metabolic activityvia the reduction of tetrazolium salts to formazon salts. WST-1 (RocheCat #11 644 807 001) was used to measure the proliferation of PC-3cells. PC-3 cells were plated in 180 μL of growth media (F-12 Kaighns'supplemented with 10% Fetal Bovine Serum and 1% Penicillin/Streptomycin)at 3000 cells per well. The plated cells were incubated overnight in 5%CO₂ at 37° C. Compounds were diluted in DMSO from 10 mM stock solutionand then into F-12 Kaighns medium. 20 μL of compound dilutions includingthe DMSO control in triplicate were added to the cells in the 96-wellplate. The cells were incubated with compound for 3 days in 5% CO₂ at37° C. 20 μL of WST-1 was added to each well. The plates were incubatedfor two hours in 5% CO₂ at 37° C. The plates were read on a Victor 2multilabel plate reader (Perkin Elmer) at 450 nm. IC₅₀ values werecalculated compared to the DMSO control.

Heteroaryl Compounds have, or are expected to have, an IC₅₀ below 30 μMin this assay, with some compounds having an IC₅₀ below 1 μM, and othershaving an IC₅₀ below 0.10 μM.

IL-2 Inflammation Assay.

The following is an example of an assay that can be used to determinethe anti-inflammatory activity of a test compound. IL-2 production fromstimulated primary T cells was assayed using the IL-2 kit from Mesoscale(MA6000#L41AHB-1). Human primary T cells were pretreated with compoundfor 30 minutes and then stimulated with anti-human CD3 beads and antiCD28 beads for 24 hours. After cell treatment, the media was harvested.25 μL of sample or calibration standard was added to human IL-2 cytokineMesoscale Assay plate. The media was incubated for 1-2 hours withshaking at room temperature. The plates were washed three times with1×PBS. 150 μL of 2XMSD Read buffer T was added per well and the platewas analyzed on Mesoscale Discovery Sector Imager plate reader.

Heteroaryl Compounds have, or are expected to have, an IC₅₀ below 30 μMin this assay, with some compounds having an IC₅₀ below 1 μM, and othershaving an IC₅₀ below 0.10 μM.

5.2.3 In Vivo Models

Delayed-Type Hypersensitivity (DTH) Model.

On day 0, CD-1 mice were sensitized using 3% oxazolone, painted on theshaved abdomen (sensitization). On day 5 the right ear was painted with1% oxazolone and the left ear was painted with vehicle (acetone:oliveoil) (elicitation). Compound treatment was started one day prior to the1% oxazolone elicitation step. Compounds were administered eitherorally, intraperitoneally, or intravenously, using once or twice dailydosing for the duration of the study. On day 6 (24 hr post elicitation)the right ear of untreated animals showed redness (erythema) andswelling (edema). The ears of compound-treated animals were measured 24,48 and 72 hr post elicitation. Differences between right and left earthickness, indicating DTH development was determined by microcalipermeasurements.

In this model, Heteroaryl Compounds have, or are expected to have, anED₅₀ value of <100 mg/kg, with some compounds having an ED₅₀ of <10mg/kg and others an ED₅₀ of <1 mg/kg.

Xenograft Cancer Model.

Human cancer cell lines were injected into SCID (severe combinedimmunodeficiency) mice. For cells maintained in vitro, tumors weregenerated by injecting precisely determined numbers of cells into mice.For tumors which were best propagated in vivo, tumor fragments fromdonor mice were implanted into small numbers of mice for maintenance, orlarger numbers of mice for study initiation. A typical efficacy studydesign involved administering one or more compounds to tumor-bearingmice. Additionally, reference chemotherapeutic agents (positive control)and negative controls were similarly administered and maintained. Routesof administration can include subcutaneous (SC), intraperitoneal (IP),intravenous (IV), intramuscular (IM) and oral (PO). Tumor measurementsand body weights were taken over the course of the study and morbidityand mortality were recorded. Necropsy, histopathology, bacteriology,parasitology, serology and PCR can also be performed to enhanceunderstanding of disease and drug action.

Some of the typical human cancer cell lines that were or can be used inthe above xenograft models are: the MDA MB-231, MCF7, MDA-MB-435, andT-47D cell lines for breast cancer; the KM 12, HCT-15, COLO 205, HCT 116and HT29 cell lines for colon cancer; the NC1-H460 and A549 cell linesfor lung cancer; the CRW22, LNCAP, PC-3, and DU-145 cell lines forprostate cancer; the LOX-IMVI and A375 cell lines for melanoma; the SK-OV-3 and A2780 cell lines for ovarian cancer; and the CAKI-I, A498, andSN12C cell lines for renal cancer; and U-87MG cell line for gliomacancer.

In short, SCID mice were dosed with compounds ranging from, for example,100 mg/kg to 0.1 mg/kg with different dose scheduling, including, butnot limited to, qd, q2d, q3d, q5d and bid. The compounds were formulatedin, for example 0.5% CMC/0.25% Tween and delivered orally. The mice weredosed for 21 days and tumor volume measurements were taken every threedays. Example Xenograft models tested included PC-3, HCT-116, A549, MDAMB-231 and U-87MG models.

In this model, Heteroaryl Compounds have, or are expected to have, anED₅₀ value of <100 mg/kg, with some compounds having an ED₅₀ of <10mg/kg and others an ED₅₀ of <1 mg/kg.

5.3 Heteroaryl Compound Activity

Each of the compounds in Table 1 was tested in the mTor HTR-FRET assayand was found to have activity therein, with all of the compounds havingan IC₅₀ below 10 μM in the assay, with some compounds having an IC₅₀between and 0.005 nM and 250 nM (Activity level D), others having anIC₅₀ between and 250 nM and 500 nM (Activity level C), others having anIC₅₀ between 500 nM and 1 μM (Activity level B), and others having anIC₅₀ between 1 μM and 10 μM (Activity level A).

TABLE 1 Cmpd MS (ESI) Act. No. Cmpd Structure Cmpd Name m/z Level 1

6-(1H-pyrrolo[2,3-b]pyridin- 3-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 379.3[M + 1]⁺ D 2

6-(4-methyl-6-(1H-1,2,4- triazol-3-yl)pyridin-3-yl)-4-((tetrahydro-2H-pyran-4- yl)methyl)-3,4- dihydropyrazino[2,3-b]pyrazin-2(1H)-one 407.1 [M + 1]⁺ D 3

6-(5-fluoro-2-methyl-4-(1H- 1,2,4-triazol-3-yl)phenyl)-4- ((trans-4-methoxycyclohexyl)methyl)- 3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one452.2 [M + 1]⁺ D 4

6-(5-fluoro-2-methyl-4-(1H- 1,2,4-triazol-3-yl)phenyl)-4- ((cis-4-methoxycyclohexyl)methyl)- 3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one452.2 [M + 1]⁺ D 5

6-(6-(1H-1,2,4-triazol-3- yl)pyridin-3-yl)-4-((trans-4-methoxycyclohexyl)methyl)- 3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one421.3 [M + 1]⁺ D 6

6-(5-fluoro-2-methyl-4-(1H- 1,2,4-triazol-3-yl)phenyl)-4- ((trans-4-hydroxycyclohexyl)methyl)- 3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one438.1 [M + 1]⁺ D 7

6-(6-(1H-1,2,4-triazol-3- yl)pyridin-3-yl)-4-((cis-4-methoxycyclohexyl)methyl)- 3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one421.2 [M + 1]⁺ D 8

6-(6-(1H-1,2,4-triazol-3- yl)pyridin-3-yl)-4-((trans-4-hydroxycyclohexyl)methyl)- 3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one407.1 [M + 1]⁺ D 9

6-(6-(1H-1,2,4-triazol-3- yl)pyridin-3-yl)-4-(cis-4-hydroxycyclohexyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 393.2[M + 1]⁺ D 10

6-(6-(1H-1,2,4-triazol-3- yl)pyridin-3-yl)-4-((cis-4-hydroxycyclohexyl)methyl)- 3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one407.3 [M + 1]⁺ D 11

6-(5-fluoro-2-methyl-4-(1H- 1,2,4-triazol-3-yl)phenyl)-4-(trans-4-methoxycyclohexyl)- 3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one 438.2 [M + 1]⁺ D 12

6-(6-(1H-1,2,4-triazol-3- yl)pyridin-3-yl)-4-(trans-4-methoxycyclohexyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 407.2[M + 1]⁺ D 13

6-(6-(1H-1,2,4-triazol-3- yl))pyridin-3-yl)-4-(trans-4-hydroxycyclohexyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 393.2[M + 1]⁺ D 14

6-(5-fluoro-2-methyl-4-(1H- 1,2,4-triazol-3-yl)phenyl)-4- ((cis-4-hydroxycyclohexyl)methyl)- 3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one438.2 [M + 1]⁺ D 15

6-(6-(1H-1,2,4-triazol-3- yl)pyridin-3-yl)-4-(cis-4-methoxycyclohexyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 407.3[M + 1]⁺ D 16

6-(6-(1H-1,2,4-triazol-3- yl)pyridin-3-yl)-4-(2- methoxyethyl)-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 353.2 [M + 1]⁺ D 17

6-(6-(1H-1,2,4-triazol-3- yl)pyridin-3-yl)-4-isopropyl-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 337.1 [M + 1]⁺ D 18

6-(5-fluoro-2-methyl-4-(1H- 1,2,4-triazol-3-yl)phenyl)-4-(cis-4-hydroxycyclohexyl)- 3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one424.2 [M + 1]⁺ D 19

6-(5-fluoro-2-methyl-4-(1H- 1,2,4-triazol-3-yl)phenyl)-4-(cis-4-methoxycyclohexyl)- 3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one438.3 [M + 1]⁺ D 20

6-(5-fluoro-2-methyl-4-(1H- 1,2,4-triazol-3-yl)phenyl)-4-(2-methoxyethyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 384.2[M + 1]⁺ D 21

6-(6-(1H-1,2,4-triazol-3- yl)pyridin-3-yl)-4-(tetrahydro-2H-pyran-4-yl)- 3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one379.1 [M + 1]⁺ D 22

6-(6-(1H-1,2,4-triazol-3- yl)pyridin-3-yl)-4-ethyl-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 323.1 [M + 1]⁺ D 23

6-(5-fluoro-2-methyl-4-(1H- 1,2,4-triazol-3-yl)phenyl)-4-(trans-4-hydroxycyclohexyl)- 3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one 424.2 [M + 1]⁺ D 24

6-(5-fluoro-2-methyl-4-(1H- 1,2,4-triazol-3-yl)phenyl)-4-(tetrahydro-2H-pyran-4-yl)- 3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one410.1 [M + 1]⁺ D 25

6-(5-fluoro-2-methyl-4-(lH- 1,2,4-triazol-3-yl)phenyl)-4- isopropyl-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 368.1 [M + 1]⁺ D 26

4-ethyl-6-(5-fluoro-2-methyl- 4-(1H-1,2,4-triazol-3- yl)phenyl)-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 354.2 [M + 1]⁺ D 27

6-(3-fluoro-2-methyl-4-(1H- 1,2,4-triazol-3-yl)phenyl)-4-(tetrahydro-2H-pyran-4-yl)- 3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one409.7 [M + 1]⁺ D 28

6-(3-fluoro-2-methyl-4-(1H- l,2,4-triazol-3-yl)phenyl)-4-(cis-4-methoxycyclohexyl)- 3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one437.7 [M + 1]⁺ D 29

6-(3-fluoro-2-methyl-4-(1H- 1,2,4-triazol-3-yl)phenyl)-4-(trans-4-methoxycyclohexyl)- 3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one 438.0 [M + 1]⁺ D 30

4-(2-methoxyethyl)-6-(4- methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 367.4[M + 1]⁺ D 31

6-(3-(1H-1,2,4-triazol-5- yl(phenyl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 406.2[M + 1]⁺ A 32

5-(8-(2-methoxyethyl)-6-oxo- 5,6,7,8- tetrahydropyrazino[2,3-b]pyrazin-2-yl)-4- methylpicolinamide 397.4 [M + 1]⁺ D 33

3-(6-oxo-8-(2-(tetrahydro-2H- pyran-4-yl)ethyl)-5,6,7,8-tetrahydropyrazino[2,3- b]pyrazin-2-yl)benzamide 382.1 [M + 1]⁺ B 34

3-(6-oxo-8-(2-(tetrahydro-2H- pyran-4-yl)ethyl)-5,6,7,8-tetrahydropyrazino[2,3- b]pyrazin-2-yl)benzonitrile 364.8 [M + 1]⁺ B 35

5-(8-(trans-4- methoxycyclohexyl)-6-oxo- 5,6,7,8-tetrahydropyrazino[2,3- b]pyrazin-2-yl)-4- methylpicolinamide 397.4 [M +1]⁺ D 36

6-(1H-imidazo[4,5-b]pyridin- 6-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 380.2[M + 1]⁺ B 37

6-(1H-indazol-6-yl)-4-(2- (tetrahydro-2H-pyran-4- yl)ethyl)-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 379.5 [M + 1]⁺ A 38

4-((1R,3S)-3- methoxycyclopentyl)-6-(2- methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 407.3[M + 1]⁺ D 39

4-((1S,3R)-3- methoxycyclopentyl)-6-(2- methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 407.3[M + 1]⁺ D 40

4-((1R,3R)-3- methoxycyclopentyl)-6-(2- methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 407.3[M + 1]⁺ D 41

4-((1S,3S)-3- methoxycyclopentyl)-6-(2- methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 407.3[M + 1]⁺ D 42

4-ethyl-6-(2-methyl-6-(4H- 1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 337.7 [M + 1]⁺ D 43

6-(1H-pyrrolo[2,3-b]pyridin- 5-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 379.2[M + 1]⁺ D 44

6-(1H-indol-6-yl)-4-(2- (tetrahydro-2H-pyran-4- yl)ethyl)-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 378.1 [M + 1]⁺ C 45

6-(1H-indol-5-yl)-4-(2- (tetrahydro-2H-pyran-4- yl)ethyl)-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 378.1 [M + 1]⁺ D 46

4-(((1R,3S)-3- methoxycyclopentyl)methyl)- 6-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one421.2 [M + 1]⁺ D 47

4-(((1S,3R)-3- methoxycyclopentyl)methyl)- 6-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one421.2 [M + 1]⁺ D 48

6-(3-fluoro-2-methyl-4-(4H- 1,2,4-triazol-3-yl)phenyl)-4-(2-(tetrahydro-2H-pyran-4- yl)ethyl)-3,4- dihydropyrazino[2,3-b]pyrazin-2(1H)-one 438.3 [M + 1]⁺ D 49

6-(3-fluoro-2-methyl-4-(4H- 1,2,4-triazol-3-yl)phenyl)-4-(2-methoxyethyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 384.3[M + 1]⁺ D 50

3,3-dimethyl-6-(4-methyl-6- (4H-1,2,4-triazol-3- yl)pyridin-3-yl)-4-((tetrahydro-2H-pyran-4- yl)methyl)-3,4- dihydropyrazino[2,3-b]pyrazin-2(1H)-one 435.3 [M + 1]⁺ D 51

6-(6-(2-hydroxypropan-2- yl)pyridin-3-yl)-4-((1R,3S)-3-methoxycyclopentyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 384.3[M + 1]⁺ D 52

6-(6-(2-hydroxypropan-2- yl)pyridin-3-yl)-4-((1S,3R)-3-methoxycyclopentyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 384.3[M + 1]⁺ D 53

6-(6-(2-hydroxypropan-2- yl)pyridin-3-yl)-4-(((1S,3S)- 3-methoxycyclopentyl)methyl)- 3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one398.3 [M + 1]⁺ D 54

6-(6-(2-hydroxypropan-2- yl)pyridin-3-yl)-4-(((1R,3R)- 3-methoxycyclopentyl)methyl)- 3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one398.3 [M + 1]⁺ D 55

6-(6-(2-hydroxypropan-2- yl)pyridin-3-yl)-4-((1S,3S)-3-methoxycyclopentyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 384.3[M + 1]⁺ A 56

6-(6-(2-hydroxypropan-2- yl)pyridin-3-yl)-4-((1R,3R)-3-methoxycyclopentyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 384.3[M + 1]⁺ D 57

6-(6-(2-hydroxypropan-2- yl)pyridin-3-yl)-4-(((1R,3S)- 3-methoxycyclopentyl)methyl)- 3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one398.3 [M + 1]⁺ D 58

6-(6-(2-hydroxypropan-2- yl)pyridin-3-yl)-4-(((1S,3R)- 3-methoxycyclopentyl)methyl)- 3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one398.3 [M + 1]⁺ D 59

6-(3-fluoro-4-(4H-1,2,4- triazol-3-yl)phenyl)-4-(2- methoxyethyl)-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 370.2 [M + 1]⁺ D 60

6-(3-fluoro-4-(4H-1,2,4- triazol-3-yl)phenyl)-4-(2-(tetrahydro-2H-pyran-4- yl)ethyl)-3,4- dihydropyrazino[2,3-b]pyrazin-2(1H)-one 424.3 [M + 1]⁺ D 61

7′-(2-methyl-4-(4H-1,2,4- triazol-3-yl)phenyl)-1′-((tetrahydro-2H-pyran-4- yl)methyl)-1′H- spiro[cyclopentane-1,2′-pyrazino[2,3-b]pyrazin]- 3′(4′H)-one 460.4 [M + 1]⁺ D 62

7′-(2-methyl-4-(4H-1,2,4- triazol-3-yl)phenyl)-1′-((tetrahydro-2H-pyran-4- yl)methyl)-1′H- spiro[cyclobutane-1,2′-pyrazino[2,3-b]pyrazin]- 3′(4′H)-one 446.4 [M + 1]⁺ D 63

4-(cyclopropylmethyl)-6-(6- (2-hydroxypropan-2- yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 340.2 [M + 1]⁺ C 64

7′-(2-methyl-4-(4H-1,2,4 triazol-3-yl)phenyl)-1′H-spiro[cyclopentane-1,2′- pyrazino[2,3-b]pyrazin]- 3′(4′H)-one 362.3 [M +1]⁺ C 65

7'-(2-methyl-4-(4H-1,2,4- triazol-3-yl)phenyl)-1'H-spiro[cyclobutane-l,2'- pyrazino[2,3-b]pyrazin]- 3'(4,H)-one 348.2 [M +1]⁺ C 66

7′-(2-methyl-4-(4H-1,2,4- triazol-3-yl)phenyl)-1′H-spiro[cyclopropane-1,2′- pyrazino[2,3-b]pyrazin]- 3′(4′H)-one 334.2 [M +1]⁺ D 67

(R)-6-(4-(4H-1,2,4-triazol-3- yl)phenyl)-4- ((tetrahydrofuran-2-yl)methyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 378.1 [M + 1]⁺.D 68

(S)-6-(4-(4H-1,2,4-triazol-3- yl)phenyl)-4- ((tetrahydrofuran-2-yl)methyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 378.1 [M + 1]⁺D 69

6-(1H-indazol-5-yl)-4-(2- (tetrahydro-2H-pyran-4- yl)ethyl)-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 379.0 [M + 1]⁺ C 70

4-(6-oxo-8-(2-(tetrahydro-2H- pyran-4-yl)ethyl)-5,6,7,8-tetrahydropyrazino[2,3- b]pyrazin-2-yl)benzamide 382.5 [M + 1]⁺ A 71

4-(2-methoxyethyl)-3,3- dimethyl-6-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one394.2 [M + 1]⁺ D 72

4-ethyl-3,3-dimethyl-6-(2- methyl-4-(4H-1,2,4-triazol-3- yl)phenyl)-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 364.2 [M + 1]⁺ D 73

6-(2-methyl-4-(4H-1,2,4- triazol-3-yl)phenyl)-3,4- dihydropyrazino[2,3-b]pyrazin-2(1H)-one 308.1 [M + 1]⁺ C 74

3,3-dimethyl-6-(2-methyl-6- (4H-1,2,4-triazol-3- yl)pyridin-3-yl)-4-((tetrahydro-2H-pyran-4- yl)methyl)-3,4- dihydropyrazino[2,3-b]pyrazin-2(1H)-one 435.3 [M + 1]⁺ D 75

(R)-6-(6-(1- hydroxyethyl)pyridin-3-yl)-4- (2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 384.3 [M + 1]⁺ D76

3,3-dimethyl-6-(2-methyl-4- (4H-1,2,4-triazol-3-yl)phenyl)-4-((tetrahydro-2H- pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 434.2 [M + 1]⁺ D 77

6-(6-(2-hydroxypropan-2-yl)- 4-methylpyridin-3-yl)-4-(trans-4-methoxycyclohexyl)- 3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one 412.4 [M + 1]⁺ D 78

6-(6-(2-hydroxypropan-2-yl)- 4-methylpyridin-3-yl)-4-((tetrahydro-2H-pyran-4- yl)methyl)-3,4- dihydropyrazino[2,3-b]pyrazin-2(1H)-one 398.3 [M + 1]⁺ D 79

3,3-dimethyl-6-(2-methyl-4- (4H-1,2,4-triazol-3- yl)phenyl)-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 336.2 [M + 1]⁺ C 80

3,3-dimethyl-6-(2-methyl-6- (4H-1,2,4-triazol-3- yl)pyridin-3-yl)-4-(2-(tetrahydro-2H-pyran-4- yl)ethyl)-3,4- dihydropyrazino[2,3-b]pyrazin-2(1H)-one 449.2 [M + 1]⁺ D 81

6-(6-(2-hydroxypropan-2-yl)- 2-methylpyridin-3-yl)-4-((tetrahydro-2H-pyran-4- yl)methyl)-3,4- dihydropyrazino[2,3-b]pyrazin-2(1H)-one 398.5 [M + 1]⁺ D 82

6-(6-(2-hydroxypropan-2-yl)- 2-methylpyridin-3-yl)-4-(trans-4-methoxycyclohexyl)- 3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one 412.5 [M + 1]⁺ C 83

(S)-6-(6-(1- hydroxyethyl)pyridin-3-yl)-4- (2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 384.3 [M + 1]⁺ C84

3,3-dimethyl-6-(2-methyl-4- (4H-1,2,4-triazol-3-yl)phenyl)-4-(2-(tetrahydro- 2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 448.3 [M + 1]⁺ D 85

6-(6-(2-hydroxypropan-2- yl)pyridin-3-yl)-3,3-dimethyl-4-(2-(tetrahydro-2H-pyran-4- yl)ethyl)-3,4- dihydropyrazino[2,3-b]pyrazin-2(1H)-one 426.3 [M + 1]⁺ B 86

6-(4-(2-hydroxypropan-2- yl)phenyl)-4-(trans-4- methoxycyclohexyl)-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 397.2 [M + 1]⁺ D 87

6-(4-(2-hydroxypropan-2- yl)phenyl)-4-((trans-4-methoxycyclohexyl)methyl)- 3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one411.3 [M + 1]⁺ C 88

4-(cis-4-methoxycyclohexyl)- 6-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one421.2 [M + 1]⁺ D 89

4-(trans-4- methoxycyclohexyl)-6-(2- methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 421.0[M + 1]⁺ D 90

6-(4-(2-hydroxypropan-2- yl)phenyl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 383.3[M + 1]⁺ D 91

4-(2-methoxyethyl)-6-(2- methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 367.5[M + 1]⁺ D 92

9-(6-(4H-1,2,4-triazol-3-yl)- 3-pyridyl)-6,11,4a-trihydromorpholino[4,3- e]pyrazino[2,3-b]pyrazin-5- one 351.5 [M + 1]⁺ B93

6-(2-methyl-6-(4H-1,2,4- triazol-3-yl)pyridin-3-yl)-4-((tetrahydro-2H-pyran-4- yl)methyl)-3,4- dihydropyrazino[2,3-b]pyrazin-2(1H)-one 407.8 [M + 1]⁺ C 94

5-(8-(cis-4- methoxycyclohexyl)-6-oxo- 5,6,7,8- tetrahydropyrazino[2,3-b]pyrazin-2-yl)-6- methylpicolinonitrile 379.2 [M + 1]⁺ A 95

6-(6-(4H-1,2,4-triazol-3- yl)pyridin-3-yl)-4-(2- (tetrahydro-2H-pyran-4-yl)ethyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 407.3 [M + 1]⁺ D96

9-(4-(4H-1,2,4-triazol-3-yl)- 2-methylphenyl)-3-(2-methoxyacetyl)-6,11,4a- trihydropiperazino[1,2-e]pyrazino[2,3-b]pyrazin-5- one 435.3 [M + 1]⁺ D 97

9-(4-(4H-1,2,4-triazol-3-yl)- 2-methylphenyl)-6,11,4a-trihydropiperazino[1,2- e]pyrazino[2,3-b]pyrazin-5- one 363.2 [M + 1]⁺ D98

9-(4-(4H-1,2,4-triazol-3-yl)- 2-methylphenyl)-3-(2-methoxyethyl)-6,11,4a- trihydropiperazino[1,2-e]pyrazino[2,3-b]pyrazin-5- one 421.4 [M + 1]⁺ C 99

4-(cyclopentylmethyl)-6-(2- methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 391.8[M + 1]⁺ D 100

9-(6-(4H-1,2,4-triazol-3-yl)- 2-methyl-3-pyridyl)-6,11,4a-trihydromorpholino[4,3- e]pyrazino[2,3-b]pyrazin-5- one 365.5 [M + 1]⁺ C101

4-(trans-4- hydroxycyclohexyl)-6-(6-(2- hydroxypropan-2-yl)pyridin-3-yl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 384.2 [M + 1]⁺ D 102

4-(cis-4-hydroxycyclohexyl)- 6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 384.2[M + 1]⁺ C 103

6-(6-(2-hydroxypropan-2- yl)pyridin-3-yl)-4- ((tetrahydrofuran-3-yl)methyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 370.3 [M + 1]⁺B 104

4-(cyclopentylmethyl)-6-(6- (2-hydroxypropan-2- yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 368.1 [M + 1]⁺ D 105

6-(6-(2-hydroxypropan-2- yl)pyridin-3-yl)-4-neopentyl-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 356.1 [M + 1]⁺ C 106

6-(6-(2-hydroxypropan-2- yl)pyridin-3-yl)-4-isobutyl-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 342.2 [M + 1]⁺ B 107

3-methyl-6-(2-methyl-4-(4H- 1,2,4-triazol-3-yl)phenyl)-4-(2-(tetrahydro-2H-pyran-4- yl)ethyl)-3,4- dihydropyrazino[2,3-b]pyrazin-2(1H)-one 434.1 [M + 1]⁺ D 108

6-(6-(2-hydroxypropan-2- yl)pyridin-3-yl)-4-(piperidin- 4-yl)-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 369.3 [M + 1]⁺ A 109

6-(6-(2-hydroxypropan-2- yl)pyridin-3-yl)-4-(2- (tetrahydro-2H-pyran-3-yl)ethyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 398.1 [M + 1]⁺ D110

8-(4-(4H-1,2,4-triazol-3-yl)- 2-methylphenyl)(3aS,2R)-2-methoxy-5,10,3a- trihydropyrazino[2,3- b]pyrrolidino[1,2-e]pyrazin-4-one 378.2 [M + 1]⁺ N/A 111

8-(4-(4H-1,2,4-triazol-3-yl)-2-methylphenyl)(2R,3aR)-2-methoxy-5,10,3a-trihydropyrazino[2,3-b]pyrrolidino[1,2-e]pyrazin-4-one378.2 [M + 1]⁺ N/A 112

8-(4-(4H-1,2,4-triazol-3-yl)-2-methylphenyl)(2S,3aR)-2-methoxy-5,10,3a-trihydropyrazino[2,3-b]pyrrolidino[1,2-e]pyrazin-4-one 378.2 [M + 1]⁺ D 113

8-(4-(4H-1,2,4-triazol-3-yl)-2-methylphenyl)(2S,3aS)-2-methoxy-5,10,3a-trihydropyrazino[2,3-b]pyrrolidino[1,2-e]pyrazin-4-one378.2 [M + 1]⁺ C 114

6-(6-(2-hydroxypropan-2- yl)pyridin-3-yl)-4-(3- methoxypropyl)-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 358.4 [M + 1]⁺ A 115

(S)-6-(6-(2-hydroxypropan-2- yl)pyridin-3-yl)-4- ((tetrahydrofuran-2-yl)methyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 370.3 [M + 1]⁺A 116

(R)-6-(6-(2-hydroxypropan-2- yl)pyridin-3-yl)-4- ((tetrahydrofuran-2-yl)methyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 370.3 [M + 1]⁺B 117

6-(2-methyl-6-(4H-1,2,4- triazol-3-yl)pyridin-3-yl)-4-(2-(tetrahydro-2H-pyran-4- yl)ethyl)-3,4- dihydropyrazino[2,3-b]pyrazin-2(1H)-one 421.1 [M + 1]⁺ D 118

9-(4-(4H-1,2,4-triazol-3-yl)- 2-methylphenyl)-3-methyl- 6,11,4a-trihydropiperdzino[1,2- c]pyrazino[2,3-b]pyrazin-5- one 377.4 [M + 1]⁺ B119

9-(4-(4H-1,2,4-triazol-3- yl)phenyl)-6,11,4a- trihydromorpholino[4,3-e]pyrazino[2,3-b]pyrazin-5- one 350.5 [M + 1]⁺ D 120

9-(4-(4H-1,2,4-triazol-3-yl)- 2-methylphenyl)-6,11,4a-trihydropiperidino[1,2- e]pyrazino[2,3-b]pyrazin-5- one 362.1 [M + 1]⁺ D121

6-(6-(2-hydroxypropan-2- yl)pyridin-3-yl)-4-(trans-4-methoxycyclohexyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 398.3[M + 1]⁺ D 122

6-(6-(2-hydroxypropan-2- yl)pyridin-3-yl)-4-(cis-4-methoxycyclohexyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 398.2[M + 1]⁺ C 123

6-(6-(2-hydroxypropan-2- yl)pyridin-3-yl)-4-(2- morpholinoethyl)-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 399.2 [M + 1]⁺ A 124

6-(6-(2-hydroxypropan-2- yl)pyridin-3-yl)-4-phenethyl-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 390.2 [M + 1]⁺ C 125

6-(6-(2-hydroxypropan-2- yl)pyridin-3-yl)-4- (tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 370.3 [M + 1]⁺ B 126

4-(cyclohexylmethyl)-6-(6-(2- hydroxypropan-2-yl)pyridin- 3-yl)-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 382.3 [M + 1]⁺ D 127

6-(6-(2-hydroxypropan-2- yl)pyridin-3-yl)-4-((trans-4-methoxycyclohexyl)methyl)- 3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one412.2 [M + 1]⁺ D 128

6-(6-(2-hydroxypropan-2- yl)pyridin-3-yl)-4-((cis-4-methoxycyclohexyl)methyl)- 3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one412.2 [M + 1]⁺ D 129

(R)-6-(6-(2-hydroxypropan-2- yl)pyridin-3-yl)-4-(tetrahydrofuran-3-yl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one356.2 [M + 1]⁺ B 130

(S)-6-(6-(2-hydroxypropan-2- yl)pyridin-3-yl)-4-(tetrahydrofuran-3-yl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one356.1 [M + 1]⁺ B 132

(S)-6-(6-(2-hydroxypropan-2- yl)pyridin-3-yl)-3-methyl-4-(2-(tetrahydro-2H-pyran-4- yl)ethyl)-3,4- dihydropyrazino[2,3-b]pyrazin-2(1H)-one 412.3 [M + 1]⁺ D 133

9-[6-(1-hydroxy-isopropyl)-3-pyridyl]-6,11,4a-trihydromorpholino[4,3-e]pyrazino[2,3-b]pyrazin-5-one 342.0 [M + 1]⁺ B 134

6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one 384.2 [M + 1]⁺ C 135

6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one 344.1 [M + 1]⁺ A 136

6-(2-amino-7-methyl-1H- benzo[d]imidazol-5-yl)-4-(3-(trifluoromethyl)benzyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one454.4 [M + 1]⁺ B 137

6-(6-(2-hydroxypropan-2- yl)pyridin-3-yl)-4-(3-(trifluoromethyl)benzyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one444.4 [M + 1]⁺ D 138

9-(4-(4H-1,2,4-triazol-3-yl)- 2-methylphenyl)-6,11,4a-trihydromorpholino[4,3- e]pyrazino[2,3-b]pyrazin-5- one 364 [M + 1]⁺ D139

6-(4-methyl-2- (methylamino)-1H- benzo[d]imidazol-6-yl)-4-(2-(tetrahydro-2H-pyran-4- yl)ethyl)-3,4- dihydropyrazino[2,3-b]pyrazin-2(1H)-one 422.2 [M + 1]⁺ D 140

8-(4-(4H-1,2,4-triazol-3-yl)- 2-methylphenyl)-5,10,3a-trihydropyrazino[2,3- b]pyrrolidino[1,2-e]pyrazin-4- one 348.3 [M + 1]⁺D 141

6-(4-(4H-1,2,4-triazol-3- yl)phenyl)-4-ethyl-3,4- dihydropyrazino[2,3-b]pyrazin-2(1H)-one 322.2 [M + 1]⁺ C 142

6-(4-(4H-1,2,4-triazol-3- yl)phenyl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 392.3[M + 1]⁺ D 143

6-(6-(2-hydroxypropan-2- yl)pyridin-3-yl)-4-(2- (tctrahydro-2H-pyran-4-yl)ethyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 398.3 [M + 1]⁺ D144

6-(4-(4H-1,2,4-triazol-3- yl)phenyl)-4-(2- methoxyethyl)-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 352.2 [M + 1]⁺ D 145

6-(4-(4H-1,2,4-triazol-3- yl)phenyl)-4-(3- (trifluoromethyl)benzyl)-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 420.3 [M + 1]⁺ D 146

6-(2-methyl-4-(4H-1,2,4- triazol-3-yl)phenyl)-4-(2-(tetrahydro-2H-pyran-4- yl)ethyl)-3,4- dihydropyrazino[2,3-b]pyrazin-2(1H)-one 420.3 [M + 1]⁺ D 147

6-(4-methyl-1H- benzo[d]imidazol-6-yl)-4-(2- (tetrahydro-2H-pyran-4-yl)ethyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 393.3 [M + 1]⁺ B148

6-(4-(2-hydroxypropan-2- yl)phenyl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 397.2[M + 1]⁺ D 149

6-(4-(1H-1,2,4-triazol-5- yl)phenyl)-4-(2-(tetrahydro2H-pyran-4-yl)ethyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 406.2[M + 1]⁺ D 150

7-(5-fluoro-2-methyl-4-(1H- 1,2,4-triazol-3-yl)phenyl)-1- ((trans-4-methoxycyclohexyl)methyl)- 3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one452.3 [M + 1]⁺ D 151

7-(6-(1H-1,2,4-triazol-3- yl)pyridin-3-yl)-1-(cis-4-methoxycyclohexyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 407.3[M + 1]⁺ D 152

7-(1H-pyrrolo[2,3-b]pyridin- 3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 379.1[M + 1]⁺ D 153

7-(5-fluoro-2-methyl-4-(1H- 1,2,4-triazol-3-yl)phenyl)-1- ((cis-4-methoxycyclohexyl)methyl)- 3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one452.3 [M + 1]⁺ D 154

1-ethyl-7-(1H-pyrrolo[3,2- b]pyridin-5-yl)-3,4- dihydropyrazino[2,3-b]pyrazin-2(1H)-one 295.1 [M + 1]⁺ A 155

7-(6-(1H-1,2,4-triazol-3- yl)pyridin-3-yl)-1-((cis-4-methoxycyclohexyl)methyl)- 3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one421.4 [M + 1]⁺ D 156

7-(1H-benzo[d]imidazol-4- yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 379.2[M + 1]⁺ B 157

7-(1H-pyrrolo[2,3-b]pyridin- 4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 379.2[M + 1]⁺ D 158

7-(6-(1H-1,2,4-triazol-3- yl)pyridin-3-yl)-1-((trans-4-methoxycyclohexyl)methyl)- 3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one421.3 [M + 1]⁺ D 159

7-(6-(1H-1,2,4-triazol-3- yl)pyridin-3-yl)-1-((trans-4-hydroxycyclohexyl)methyl)- 3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one407.2 [M + 1]⁺ D 160

7-(6-(1H-1,2,4-triazol-3- yl)pyridin-3-yl)-1-(cis-4-hydroxycyclohexyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 393.3[M + 1]⁺ D 161

7-(5-fluoro-2-methyl-4-(1H- 1,2,4-triazol-3-yl)phenyl)-1-(cis-4-hydroxycyclohexyl)- 3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one424.2 [M + 1]⁺ D 162

7-(6-(1H-1,2,4-triazol-3- yl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)- 3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one379.2 [M + 1]⁺ D 163

7-(6-(1H-1,2,4-triazol-3- yl)pyridin-3-yl)-1-(2- methoxyethyl)-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 353.2 [M + 1]⁺ D 164

7-(6-(1H-1,2,4-triazol-3- yl)pyridin-3-yl)-1-ethyl-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 323.2 [M + 1]⁺ D 165

7-(5-fluoro-2-methyl-4-(1H- 1,2,4-triazol-3-yl)phenyl)-1- ((cis-4-hydroxycyclohexyl)methyl)- 3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one438.1 [M + 1]⁺ D 166

7-(5-fluoro-2-methyl-4-(1H- 1,2,4-triazol-3-yl)phenyl)-1-(tetrahydro-2H-pyran-4-yl)- 3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one410.3 [M + 1]⁺ D 167

7-(1H-indol-4-yl)-1-(2- (tetrahydro-2H-pyran-4- yl)ethyl)-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 378.2 [M + 1]⁺ C 168

7-(5-fluoro-2-methyl-4-(1H- l,2,4-triazol-3-yl)phenyl)-1- ((trans-4-hydroxycyclohexyl)methyl)- 3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one438.2 [M + 1]⁺ D 169

7-(6-(1H-1,2,4-triazol-3- yl)pyridin-3-yl)-1-((cis-4-hydroxycyclohexyl)methyl)- 3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one407.1 [M + 1]⁺ D 170

7-(6-(1H-1,2,4-triazol-3- yl)pyridin-3-yl)-1-(trans-4-hydroxycyclohexyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 393.2[M + 1]⁺ D 171

7-(6-(1H-1,2,4-triazol-3- yl)pyridin-3-yl)-1-(trans-4-methoxycyclohexyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 407.3[M + 1]⁺ D 172

7-(6-(1H-1,2,4-triazol-3- yl)pyridin-3-yl)-1-isopropyl-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 337.1 [M + 1]⁺ D 173

7-(5-fluoro-2-methyl-4-(1H- 1,2,4-triazol-3-yl)phenyl)-1-(trans-4-methoxycyclohexyl)- 3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one 438.3 [M + 1]⁺ D 174

7-(5-fluoro-2-methyl-4-(1H- 1,2,4-triazol-3-yl)phenyl)-1-(trans-4-hydroxycyclohexyl)- 3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one 424.3 [M + 1]⁺ D 175

7-(5-fluoro-2-methyl-4-(1H- 1,2,4-triazol-3-yl)phenyl)-1-(2-methoxyethyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 368.2[M + 1]⁺ D 176

7-(5-fluoro-2-methyl-4-(1H- 1,2,4-triazol-3-yl)phenyl)-1- isopropyl-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 323.2 [M + 1]⁺ D 177

1-ethyl-7-(5-fluoro-2-methyl- 4-(1H-1,2,4-triazol-3- yl)phenyl)-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 354.2 [M + 1]⁺ D 178

7-(2-hydroxypyridin-4-yl)-1- (2-(tetrahydro-2H-pyran-4- yl)ethyl)-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 356.1 [M + 1]⁺ B 179

1-isopropyl-7-(4-methyl-6- (1H-1,2,4-triazol-3- yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 351.4 [M + 1]⁺ D 180

5-(8-isopropyl-7-oxo-5,6,7,8- tetrahydropyrazino[2,3- b]pyrazin-2-yl)-4-methylpicolinamide 327.4 [M + 1]⁺ D 181

7-(1H-indazol-4-yl)-1-(2- (tetrahydro-2H-pyran-4- yl)ethyl)-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 379.2 [M + 1]⁺ D 182

7-(2-aminopyrimidin-5-yl)-1- (2-(tetrahydro-2H-pyran-4- yl)ethyl)-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 355.1 [M + 1]⁺ C 183

7-(2-aminopyridin-4-yl)-1-(2- (tetrahydro-2H-pyran-4- yl)ethyl)-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 355.2 [M + 1]⁺ B 184

7-(6-(methylamino)pyridin-3- yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 369.3[M + 1]⁺ D 185

7-(6-hydroxypyridin-3-yl)-1- (2-(tetrahydro-2H-pyran-4- yl)ethyl)-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 356.2 [M + 1]⁺ A 186

7-(4-(1H-pyrazol-3- yl)phenyl)-1-(2- methoxyethyl)-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 351.3 [M + 1]⁺ D 187

7-(pyridin-3-yl)-1-(2- (tetrahydro-2H-pyran-4- yl)ethyl)-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 340.1 [M + 1]⁺ B 188

7-(1H-indazol-4-yl)-1-(2- methoxyethyl)-3,4- dihydropyrazino[2,3-b]pyrazin-2(1H)-one 325.0 [M + 1]⁺ A 189

7-(1H-indazol-6-yl)-1-(2- methoxyethyl)-3,4- dihydropyrazino[2,3-b]pyrazin-2(1H)-one 324.7 [M + 1]⁺ A 190

7-(pyrimidin-5-yl)-1-(2- (tetrahydro-2H-pyran-4- yl)ethyl)-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 341.2 [M + 1]⁺ A 191

7-(6-methoxypyridin-3-yl)-1- (2-(tetrahydro-2H-pyran-4- yl)ethyl)-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 370.2 [M + 1]⁺ B 192

1-(2-methoxyethyl)-7-(1H- pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 325.0 [M + 1]⁺ D 193

1-ethyl-7-(1H-pyrrolo[2,3- b]pyridin-5-yl)-3,4- dihydropyrazino[2,3-b]pyrazin-2(1H)-one 295.2 [M + 1]⁺ C 194

1-ethyl-7-(1H-indazol-4-yl)- 3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one 295.2 [M + 1]⁺ A 195

7-(pyridin-4-yl)-1-(2- (tetrahydro-2H-pyran-4- yl)ethyl)-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 340.2 [M + 1]⁺ A 196

7-(6-aminopyridin-3-yl)-1-(2- (tetrahydro-2H-pyran-4- yl)ethyl)-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 355.1 [M + 1]⁺ D 197

1-methyl-7-(2-methyl-6-(4H- 1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 323.3 [M + 1]⁺ D 198

2-(2-hydroxypropan-2-yl)-5- (8-(trans-4- methoxycyclohexyl)-7-oxo-5,6,7,8- tetrahydropyrazino[2,3- b]pyrazin-2-yl)pyridine 1- oxide 414.2[M + 1]⁺ A 199

4-methyl-5-(7-oxo-8- ((tetrahydro-2H-pyran-4- yl)methyl)-5,6,7,8-tetrahydropyrazino[2,3- b]pyrazin-2-yl)picolinamide 383.4 [M + 1]⁺ A 200

5-(8-((cis-4- methoxycyclohexyl)methyl)- 7-oxo-5,6,7,8-tetrahydropyrazino[2,3- b]pyrazin-2-yl)-4- methylpicolinamide 411.5 [M +1]⁺ A 201

7-(1H-pyrazol-4-yl)-1-(2- (tetrahydro-2H-pyran-4- yl)ethyl)-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 329.4 [M + 1]⁺ A 202

1-(trans-4- methoxycyclohexyl)-7-(4- methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 421.5[M + 1]⁺ D 203

3-((7-(2-methyl-6-(4H-1,2,4- triazol-3-yl)pyridin-3-yl)-2-oxo-3,4-dihydropyrazino[2,3- b]pyrazin-1(2H)- yl)methyl)benzonitrile424.0 [M + 1]⁺ D 204

1-((trans-4- methoxycyclohexyl)methyl)- 7-(4-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one435.5 [M + 1]⁺ D 205

3-(7-oxo-8-(2-(tetrahydro-2H- pyran-4-yl)ethyl)-5,6,7,8-tetrahydropyrazino[2,3- b]pyrazin-2-yl)benzamide 382.1 [M + 1]⁺ A 206

5-(8-((trans-4- methoxycyclohexyl)methyl)- 7-oxo-5,6,7,8-tetrahydropyrazino[2,3- b]pyrazin-2-yl)-4- methylpicolinamide 411.5 [M +1]⁺ A 207

3-((7-(6-(2-hydroxypropan-2- yl)pyridin-3-yl)-2-oxo-3,4-dihydropyrazino[2,3- b]pyrazin-1(2H)- yl)methyl)benzonitrile 401.2 [M +1]⁺ D 208

7-(6-(2-hydroxypropan-2- yl)pyridin-3-yl)-1-((1R,3R)-3methoxycyclopentyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 384.2[M + 1]⁺ D 209

7-(6-(2-hydroxypropan-2- yl)pyridin-3-yl)-1-((1S,3R)-3-methoxycyclopentyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 384.1[M + 1]⁺ D 210

7-(6-(2-hydroxypropan-2- yl)pyridin-3-yl)-1-((1S,3S)-3-methoxycyclopentyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 384.1[M + 1]⁺ D 211

7-(6-(2-hydroxypropan-2- yl)pyridin-3-yl)-1-((1R,3S)-3-methoxycyclopentyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 384.1[M + 1]⁺ D 212

7-(1H-indazol-6-yl)-1-(2- (tetrahydro-2H-pyran-4- yl)ethyl)-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 379.2 [M + 1]⁺ D 213

7-(2-methyl-6-(4H-1,2,4- triazol-3-yl)pyridin-3-yl)-1-(2-morpholinoethyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 422.2[M + 1]⁺ D 214

1-(trans-4- hydroxycyclohexyl)-7-(2- methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 407.3[M + 1]⁺ D 215

1-(cis-4-hydroxycyclohexyl)- 7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one407.3 [M + 1]⁺ D 216

7-(6-(2-hydroxypropan-2- yl)pyridin-3-yl)-1-(2- morpholinoethyl)-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 399.2 [M + 1]⁺ D 217

1-isopropyl-7-(2-methyl-6- (4H-1,2,4-triazol-3- yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 351.5 [M + 1]⁺ D 218

7-(1H-imidazo[4,5-b]pyridin- 6-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 380.2[M + 1]⁺ A 219

1-((cis-4- methoxycyclohexyl)methyl)- 7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one435.5 [M + 1]⁺ D 220

1-(trans-4- hydroxycyclohexyl)-7-(6-(2- hydroxypropan-2-yl)pyridin-3-yl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 384.2 [M + 1]⁺ D 221

1-(cis-4-hydroxycyclohexyl)- 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 384.2[M + 1]⁺ D 222

4-(7-oxo-8-(2-(tetrahydro-2H- pyran-4-yl)ethyl)-5,6,7,8-tetrahydropyrazino[2,3- b]pyrazin-2-yl)benzamide 382.3 [M + 1]⁺ D 223

7-(1H-indazol-5-yl)-1-(2- (tetrahydro-2H-pyran-4- yl)ethyl)-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 379.2 [M + 1]⁺ B 224

7-(1H-pyrrolo[2,3-b]pyridin- 5-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 379.2[M + 1]⁺ D 225

7-(2-methyl-6-(4H-1,2,4- triazol-3-yl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)- 3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one393.2 [M + 1]⁺ D 226

1-((1S,3R)-3- methoxycyclopentyl)-7-(2- methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 407.5[M + 1]⁺ D 227

1-((1R,3R)-3- methoxycyclopentyl)-7-(2- methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 407.5[M + 1]⁺ D 228

1-((1R,3S)-3- methoxycyclopentyl)-7-(2- methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 407.5[M + 1]⁺ D 229

1-((1S,3S)-3- methoxycyclopentyl)-7-(2- methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 407.5[M + 1]⁺ D 230

7-(1H-indol-5-yl)-1-(2- (tetrahydro-2H-pyran-4- yl)ethyl)-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 378.2 [M + 1]⁺ D 231

1-ethyl-7-(2-methyl-6-(4H- 1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 337.6 [M + 1]⁺ D 232

7-(1H-indol-6-yl)-1-(2- (tetrahydro-2H-pyran-4- yl)ethyl)-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 378.2 [M + 1]⁺ C 233

7-(4-(2-hydroxypropan-2- yl)phenyl)-1-(trans-4- methoxycyclohexyl)-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 397.2 [M + 1]⁺ D 234

7-(6-(2-hydroxypropan-2- yl)pyridin-3-yl)-1- (tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 370.2 [M + 1]⁺ B 235

1-((trans-4- methoxycyclohexyl)methyl)- 7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one435.4 [M + 1]⁺ D 236

7-(6-(2-hydroxypropan-2- yl)pyridin-3-yl)-1-((cis-4-methoxycyclohexyl)methyl)- 3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one412.3 [M + 1]⁺ D 237

1-(2-methoxyethyl)-7-(4- methyl-2-(methylamino)-1H-benzo[d]imidazol-6-yl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one368.3 [M + 1]⁺ D 238

7-(7-methyl-2-oxo-2,3- dihydro-1H- benzo[d]imidazol-5-yl)-1-((tetrahydro-2H-pyran-4- yl)methyl)-3,4- dihydropyrazino[2,3-b]pyrazin-2(1H)-one 395.2 [M + 1]⁺ B 239

7-(2-methyl-4-(4H-1,2,4- triazol-3-yl)phenyl)-3,4- dihydropyrazino[2,3-b]pyrazin-2(1H)-one 308.3 [M + 1]⁺ D 240

1-(2-methoxyethyl)-7-(4- methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 367.4[M + 1]⁺ D 241

1-benzyl-7-(2-methyl-4-(4H- 1,2,4-triazol-3-yl)phenyl)-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 398.3 [M + 1]⁺ D 242

7-(3-fluoro-4-(4H-1,2,4- triazol-3-yl)phenyl)-1-(2- methoxyethyl)-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 370.3 [M + 1]⁺ D 243

7-(3-fluoro-4-(4H-1,2,4- triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4- yl)ethyl)-3,4- dihydropyrazino[2,3-b]pyrazin-2(1H)-one 424.2 [M + 1]⁺ D 244

7-(3-fluoro-2-methyl-4-(1H- 1,2,4-triazol-3-yl)phenyl)-1-(2-methoxyethyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 384.5[M + 1]⁺ D 245

1-(trans-4- methoxycyclohexyl)-7-(2- methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 421.2[M + 1]⁺ D 246

7-(6-(2-hydroxypropan-2- yl)pyridin-3-y1)-1-(trans-4-methoxycyclohexyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 398.3[M + 1]⁺ D 247

7-(5-fluoro-2-methyl-4-(4H- 1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4- yl)ethyl)-3,4- dihydropyrazino[2,3-b]pyrazin-2(1H)-one 438.3 [M + 1]⁺ D 248

7-(3-fluoro-2-methyl-4-(1H- 1,2,4-triazol-3-yl(phenyl)-1-(2-(tetrahydro-2H-pyran-4- yl)ethyl)-3,4- dihydropyrazino[2,3-b]pyrazin-2(1H)-one 438.6 [M + 1]⁺ D 249

1-(2-methoxyethyl)-7-(2- methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 367.2[M + 1]⁺ D 250

7-(6-(2-hydroxypropan-2- yl)pyridin-3-yl)-1-((trans-4-methoxycyclohexyl)methyl)- 3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one412.3 [M + 1]⁺ D 251

1-(cyclopentylmethyl)-7-(6- (2-hydroxypropan-2- yl)pyridin-3-yl)-3.4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 368.3 [M + 1]⁺ B 252

7-(4-(2-hydroxypropan-2- yl)phenyl)-1-(2- methoxyethyl)-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 343.2 [M + 1]⁺ A 253

(S)-7-(6-(1- hydroxyethyl)pyridin-3-yl)-1- (2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 384.3 [M + 1]⁺ D254

(R)-7-(6-(1- hydroxyethyl)pyridin-3-yl)-1- (2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 384.3 [M + 1]⁺ D255

7-(2-methyl-6-(4H-1,2,4- triazol-3-yl)pyridin-3-yl)-1-((tetrahydro-2H-pyran-4- yl)methyl)-3,4- dihydropyrazino[2,3-b]pyrazin-2(1H)-one 407.3 [M + 1]⁺ D 256

7-(4-(2-hydroxypropan-2- yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 397.2[M + 1]⁺ D 257

7-(6-(2-hydroxypropan-2- yl)pyridin-3-yl)-1-(4-(trifluoromethyl)benzyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one444.3 [M + 1]⁺ D 258

7-(6-(2-hydroxypropan-2- yl)pyridin-3-yl)-1-(3-(trifluoromethyl)benzyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one444.2 [M + 1]⁺ D 259

7-(6-(2-hydroxypropan-2- yl)pyridin-3-yl)-1-(3- methoxypropyl)-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 358.2 [M + 1]⁺ D 260

7-(4-methyl-6-(1H-1,2,4- triazol-3-yl)pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4- yl)ethyl)-3,4- dihydropyrazino[2,3-b]pyrazin-2(1H)-one 421.4 [M + 1]⁺ D 261

7-(6-(2-hydroxypropan-2- yl)pyridin-3-yl)-1-(2- methoxyethyl)-3,4-dihydropyrazino[2,3- b]pyrazin-2(1H)-one 344.3 [M + 1]⁺ A 262

7-(6-(2-hydroxypropan-2- yl)pyridin-3-yl)-1- ((tetrahydro-2H-pyran-4-yl)methyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 384.3 [M + 1]⁺A 263

7-(4-methyl-2- (methylamino)-1H- benzo[d]imidazol-6-yl)-1-((tetrahydro-2H-pyran-4- yl)methyl)-3,4- dihydropyrazino[2,3-b]pyrazin-2(1H)-one 408.3 [M + 1]⁺ D 264

7-(2-amino-4-methyl-1H- benzo[d]imidazol-6-yl)-1-((tetrahydro-2H-pyran-4- yl)methyl)-3,4- dihydropyrazino[2,3-b]pyrazin-2(1H)-one 394.2 [M + 1]⁺ D 265

7-(2-methyl-6-(4H-1,2,4- triazol-3-yl)pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4- yl)ethyl)-3,4- dihydropyrazino[2,3-b]pyrazin-2(1H)-one 421.1 [M + 1]⁺ D 266

(R)-7-(6-(2-hydroxypropan-2- yl)pyridin-3-yl)-3-methyl-1-(2-(tetrahydro-2H-pyran-4- yl)ethyl)-3,4- dihydropyrazino[2,3-b]pyrazin-2(1H)-one 412.5 [M + 1]⁺ B 267

(S)-7-(6-(2-hydroxypropan-2- yl)pyridin-3-yl)-3-methyl-1-(2-(tetrahydro-2H-pyran-4- yl)ethyl)-3,4- dihydropyrazino[2,3-b]pyrazin-2(1H)-one 412.5 [M + 1]⁺ B 269

7-(2-amino-4-methyl-1H- benzo[d]imidazol-6-yl)-1-(2-(tetrahydro-2H-pyran-4- yl)ethyl)-3,4- dihydropyrazino[2,3-b]pyrazin-2(1H)-one 408.5 [M + 1]⁺ D 270

7-(6-(2-hydroxypropan-2- yl)pyridin-3-yl)-1-(2- (tetrahydro-2H-pyran-4-yl)ethyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 398.4 [M + 1]⁺ D271

7-(2-methyl-4-(1H-1,2,4- triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4- yl)ethyl)-3,4- dihydropyrazino[2,3-b]pyrazin-2(1H)-one 420.4 [M + 1]⁺ D 272

7-(4-(1H-1,2,4-triazol-5- yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 406.0[M + 1]⁺ D 273

1-(1-hydroxypropan-2-yl)-7- (2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-oneN/A D 274

1-(2-hydroxyethyl)-7-(2- methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4- dihydropyrazino[2,3- b]pyrazin-2(1H)-one 353.3[M + 1]⁺ D

The embodiments disclosed herein are not to be limited in scope by thespecific embodiments disclosed in the examples which are intended asillustrations of a few aspects of the disclosed embodiments and anyembodiments that are functionally equivalent are encompassed by thepresent disclosure. Indeed, various modifications of the embodimentsdisclosed herein are in addition to those shown and described hereinwill become apparent to those skilled in the art and are intended tofall within the scope of the appended claims.

A number of references have been cited, the disclosures of which areincorporated herein by reference in their entirety.

What is claimed is:
 1. A compound having formula (III):

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof,wherein: X is halogen, B(OR⁺)₂ or Sn(R⁺⁺)₃; each R⁺ is independentlyhydrogen or substituted or unsubstituted C₁₋₃ alkyl, or each R⁺,together with the boron atom and the atoms to which they are attached,form a cyclic boronate; each R⁺⁺ is independently C₁₋₄ alkyl; R² is H,unsubstituted C₁₋₈ alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedheterocyclylalkyl, or substituted or unsubstituted cycloalkylalkyl; andR³ and R⁴ are each independently H, substituted or unsubstituted C₁₋₈alkyl, substituted or unsubstituted aryl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted heterocyclylalkyl, substituted or unsubstituted aralkyl,or substituted cycloalkylalkyl, wherein substituted means substitutedwith a substituent selected from the group consisting of chloro; iodo;bromo; fluoro; alkyl; hydroxy; alkoxy; alkoxyalkyl; amino; alkylamino;carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine;guanidine; enamine; aminocarbonyl; acylamino; phosphonato; phosphine;thiocarbonyl; alkylsulfonyl; sulfonamide; acyl; ester; urea; urethane;oxime; hydroxylamine; alkoxyamine; aralkoxyamine; N-oxide; hydrazine;hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate;thiocyanate; oxo; B(OH)₂, O(alkyl)aminocarbonyl; cycloalkyl, which maybe monocyclic or fused or non-fused polycyclic, or a heterocyclyl, whichmay be monocyclic or fused or non-fused polycyclic; monocyclic or fusedor non-fused polycyclic aryl or heteroaryl; aryloxy; aralkyloxy;heterocyclyloxy; and heterocyclylalkoxy.
 2. A compound having formula(VI):

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof,wherein: X is halogen, B(OR⁺)₂ or Sn(R⁺⁺)₃; each R⁺ is independentlyhydrogen or substituted or unsubstituted C₁₋₃ alkyl, or each R⁺,together with the boron atom and the atoms to which they are attached,form a cyclic boronate; each R⁺⁺ is independently C₁₋₃ alkyl; R² is H,unsubstituted C₁₋₈ alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedheterocyclylalkyl or substituted or unsubstituted cycloalkylalkyl; andR³ is H, or a substituted or unsubstituted C₁₋₈ alkyl whereinsubstituted means substituted with a substituent selected from the groupconsisting of chloro; iodo; bromo; fluoro; alkyl; hydroxy; alkoxy;alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether;imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino;phosphonato; phosphine; thiocarbonyl; alkylsulfonyl; sulfonamide; acyl;ester; urea; urethane; oxime; hydroxylamine; alkoxyamine; aralkoxyamine;N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate;isothiocyanate; cyanate; thiocyanate; oxo; B(OH)₂,O(alkyl)aminocarbonyl; cycloalkyl, which may be monocyclic or fused ornon-fused polycyclic, or a heterocyclyl, which may be monocyclic orfused or non-fused polycyclic; monocyclic or fused or non-fusedpolycyclic aryl or heteroaryl; aryloxy; aralkyloxy; heterocyclyloxy; andheterocyclylalkoxy.
 3. The compound of claim 2, wherein R² issubstituted cycloalkyl.
 4. The compound of claim 3, wherein R² issubstituted cyclohexyl.
 5. The compound of claim 4, wherein R² iscyclohexyl substituted with alkoxy.
 6. The compound of claim 5, whereinR² is cyclohexyl substituted with methoxy.
 7. The compound of claim 2,wherein X is halogen.
 8. The compound of claim 7, wherein X is Br. 9.The compound of claim 2, wherein R³ is H.
 10. The compound of claim 2,wherein X is halogen, R² is substituted cycloalkyl and R³ is H.
 11. Thecompound of claim 2, wherein the compound has the structure: